Principal metals involved in the development and progression of AD.
\r\n\t2) Human sexual disorders in males and females.
\r\n\t3) Psychological aspects of the human sexual response cycle and its disorders.
\r\n\t4) The therapeutic aspects.
\r\n\tThe human sexual response cycle and human sexual behavior are interrelated. How this inter-relationship and its association to normal sexual health need to be delineated. In a world torn between sex and sexually transmitted disease, clear-cut scientific information in the form of a monograph is required to educate.
\r\n\r\n\tHuman sexuality, gender identity, and sexuo-erotic orientation play great roles in human health and disease. Sex education is the need of the hour and a reflection will be timely.
",isbn:"978-1-80355-151-7",printIsbn:"978-1-80355-150-0",pdfIsbn:"978-1-80355-152-4",doi:null,price:0,priceEur:0,priceUsd:0,slug:null,numberOfPages:0,isOpenForSubmission:!1,isSalesforceBook:!1,hash:"13af09c4cf93ae89789a3db597972cf6",bookSignature:"Dr. Dhastagir Sultan Sheriff",publishedDate:null,coverURL:"https://cdn.intechopen.com/books/images_new/11267.jpg",keywords:"Master and Johnson's Cycle, Sex Education, Premature Ejaculation, Orgasmic Disorders, Sexual Aversion Disorders, Dyspareunia, Vaginismus, Sex Hormones, Sexually Transmitted Diseases, Impotence, Low Libido, Blood Analyses",numberOfDownloads:99,numberOfWosCitations:0,numberOfCrossrefCitations:0,numberOfDimensionsCitations:0,numberOfTotalCitations:0,isAvailableForWebshopOrdering:!0,dateEndFirstStepPublish:"August 18th 2021",dateEndSecondStepPublish:"March 3rd 2022",dateEndThirdStepPublish:"May 2nd 2022",dateEndFourthStepPublish:"July 21st 2022",dateEndFifthStepPublish:"September 19th 2022",remainingDaysToSecondStep:"3 months",secondStepPassed:!0,currentStepOfPublishingProcess:4,editedByType:null,kuFlag:!1,biosketch:"Dr. Sheriff is a life counselor, sex educationist, and researcher with over 35 years of teaching experience, five authored books, and editorials written in the British Journal of Sexology and the Journal of Royal Society of Medicine. 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AD is characterized by neuronal damage associated with an overproduction of free radicals (FRs). Although several hypotheses have been advanced to explain the memory loss that occurs in AD, the most accepted theory is that neuronal damage is associated with the presence of aggregates of the amyloid beta peptide of 42 residues (Aβ1–42) that is related to FR production.
\nIt is known that Aβ aggregation contributes to FR production because Aβ molecules are able to bind metals such as copper (cupric ion, Cu2+) that are present at high concentrations in the brains of patients with AD. Cu2+ leads to the formation of hydrogen peroxide (H2O2), which is a reactive oxygen specie (ROS). In turn, H2O2 reacts with other metals such as iron (Fe2+) through the Fenton reaction, producing the hydroxyl radical (•OH), which damages membrane lipids, proteins, and other biomolecules. Here, it is important to remember that ROS include not only FRs such as •OH, superoxide anion (O2•−), and others but also non-FRs such as H2O2, ozone (O3), and hypochlorous acid (HOCl). One hypothesis suggests that the ROS produced during AD hydrolyze a significant amount of acetylcholine (ACh), reducing cholinergic neurotransmission and thereby contributing to memory loss [1]. This has justified the use of acetylcholinesterase (AChE) inhibitors to treat AD; however, these drugs have shown limited clinical results [2].
\nBrain tissue is especially susceptible to oxidative stress due to its high aerobic metabolic activity and high lipid content. Oxidative stress is defined as the loss of cell homeostasis provoked by an imbalance between the production of prooxidant molecules (ROS) and the activity of antioxidant defense systems. Under physiological conditions, ROS are present at low concentrations in tissues, where they act as signaling molecules during cell growth, cell proliferation, redox homeostasis, and cellular signal transduction (activating tyrosine kinases, MAPKs (mitogen-activated protein kinases), or Ras protein) [3]. However, higher concentrations of ROS lead to a pathophysiological condition produced by an oxidative stress state.
\nIt has been reported that AD is associated with a high level of oxidative stress and lowered antioxidant defenses. Thus, AD may be due to the presence of FRs that alter metal metabolism and result in Aβ aggregation toxicity [4]. In recent years, considerable research has focused on the amyloid fibrils that are produced in AD, and it has been shown that the structures of these aggregates are more complex than the linear addition of monomers to fibrils; in fact, a variety of Aβ aggregates have been described. Furthermore, the amyloid fibrils cause the formation of several toxic intermediates, including soluble oligomers that bind to hippocampal neurons to produce dysfunctions in synaptic plasticity and consequently contribute to the development of AD [5]. Hence, great efforts have been made to find ways to prevent Aβ aggregation because the oligomers and fibrils are also able to activate the NADPH oxidase in microglial cells, which are “like macrophage cells” in the brain. NADPH oxidase can produce great quantities of O2•−, which is converted to H2O2; this, in turn, can participate in the Fenton reaction, producing •OH. Thus, the generation of FRs is important in AD because these have been related to its development, and Aβ and NADPH oxidase may be key targets for the treatment of this disease.
\nIn this chapter, we describe the important implications of FRs in the development and progression of AD. First, we discuss some of the principal biomolecules involved in the production of FRs in AD, emphasizing the role of Aβ1–42 due to its aggregation and its consequent implication in the formation of senile plaques when it reacts with metals to produce ROS. In addition, we explain how Aβ participates in microglial activation to produce more FRs due to the activity of NADPH oxidase. Subsequently, the reactions in which the ROS produced by Aβ and NADPH oxidase participate are described, and the relationship between FR production and the neuronal damage that occurs during AD is explained. Finally, we discuss how •OH and H2O2 production can be determined using various experimental techniques
Aβ is the principal component of extracellular deposits called amyloid plaques that are present in the brains of patients with AD. According to the amyloid cascade hypothesis, which was first established in 1991, Aβ accumulation represents the critical step in the pathophysiology of AD [6]. Aβ originates from the processing of a large transmembrane glycoprotein, amyloid precursor protein (APP). APP is a single-pass transmembrane protein with a large extracellular domain. Alternate splicing of the APP transcript generates eight isoforms, the three most common of which are the 695-amino acid form, which is expressed predominantly in the central nervous system (CNS), and the 751- and 770-amino acid forms, which are more ubiquitously expressed [7].
\nThe precise physiological function of APP is not known and remains one of the vexing issues in the field. In most studies, APP overexpression shows a positive effect on cell health and growth [8]. APP can be hydrolyzed following both the non-amyloidogenic and the amyloidogenic pathways, depending on the enzymes involved. In the non-amyloidogenic pathway, APP is hydrolyzed at amino acid residue 83 from the C-terminus by α-secretase (Figure 1). This cleavage produces a fragment of 83 amino acids (C83) and a large N-terminal ectodomain (sAPPα). C83 remains in the membrane, where it is hydrolyzed by the γ-secretase complex to produce p3, a short fragment, and the APP intracellular domain (AICD). In the amyloidogenic pathway, APP is hydrolyzed at amino acid residue 99 from the C-terminus by β-secretase to produce a fragment of 99 amino acids (C99) and an sAPPβ fragment. C99 remains in the membrane, where it is hydrolyzed by the γ-secretase complex, releasing the Aβ peptide, which consists of 42 amino acid residues (Aβ1–42), and other peptides (Figure 1) [9]. The principal difference between these two pathways is that α-secretase cleavage occurs within the Aβ region, avoiding the formation of Aβ peptide, whereas β-secretase cleavage permits Aβ formation from APP.
\nHydrolysis of APP to produce the Aβ peptide. When Aβ1–42 is released, it tends to aggregate to form oligomers and fibrils; these subsequently react with metals or with microglial cells and produce a large amount of ROS.
It is important to mention that under physiological conditions, both of these pathways occur; in fact, it has been demonstrated that Aβ is an enhancer of learning and memory and that low doses of Aβ produce presynaptic enhancement [10]. It was shown that concentrations of Aβ peptides in the picomolar-nanomolar range decrease the synthesis and release of ACh without causing neurotoxicity. The potency and reversible nature of this effect and the low concentrations of Aβ peptides found in normal brain cells suggest that Aβ-related peptides may act as modulators of cholinergic function under normal conditions [11]. However, during AD, the increase in the concentration of Aβ may be the result of an overproduction and/or a deficiency in its elimination, resulting in Aβ aggregation [12]. During the processing of APP by the amyloidogenic pathway, two principal Aβ species are produced: Aβ of 40 amino acid residues and Aβ of 42 amino acid residues (Aβ1–40 and Aβ1–42, respectively). Despite the difference of only two amino acids, the latter is more prone to aggregate; the additional amino acids give Aβ1–42 distinct thermodynamic properties [13].
\nTwo distinct mechanisms have been proposed to explain the formation of Aβ fibrils. The first invokes nucleated polymerization in which Aβ polymerization creates a nucleus to which monomers are added in an elongation process (Figure 2).
\nThe second proposed mechanism is based on a nucleated conformational conversion in which oligomers are formed as intermediates; these intermediates then form protofibrils that subsequently assemble into fibrils [14]. Because Aβ oligomers have been implied in the pathophysiology of AD, it has been proposed that the second mechanism contributes more to the progression of the disease. However, although enormous efforts have been made to understand how Aβ aggregates, principally in the form of Aβ1–42, which is more cytotoxic than Aβ1–40 [15], the mechanism by which Aβ1–42 undergoes conformational changes to form oligomers and protofibrils remains unknown (Figure 2).
\nRecently, several experimental techniques such as nuclear magnetic resonance (NMR) (solid state), Fourier transform infrared spectroscopy (FTIR), cryo-electron microscopy (cryo-EM), single-touch atomic force microscopy (AFM), and fluorescence have allowed investigators to study the Aβ1–42 fibril formation process in detail. The results suggest that a nucleated conformational conversion occurs when Aβ1–42 is present at high concentrations (>20–30 μM). The predominant oligomers formed in the early step of aggregation are dimers, tetramers, pentamers, and hexamers, but their formation is temperature- and concentration dependent. At approximately 15°C and high Aβ1–42 concentration, the formation of protofibrils from oligomers occurs more rapidly. The principal conformational change is observed in the lateral association of oligomers to yield protofibrils; this conformation involves conversion from a random coil structure to a β-sheet via an antiparallel β-hairpin intermediate [16]. The antiparallel β-hairpin has intramolecular hydrogen bonds between two hydrophobic β-strands, one with an LVFF sequence and another with a GLMVG sequence at the C-terminus. However, conversion to a β-sheet involves the rotation of β-strands to form intermolecular hydrogen bonds with other monomers in the Aβ1–42 structure. It is known that the β-strands adopt a parallel orientation in the Aβ1–42 fibrils. The β-sheet is stabilized by intermolecular hydrogen bonds as well as by intramolecular and intermolecular interactions between the residue side chains in the β-strands. It has been confirmed that the formation of the antiparallel β-hairpin is a rate-determining step in fibril formation, with the interaction between aspartate 23 (Asp23) and lysine 28 (Lys28) being the most important.
\nProposed mechanisms of Aβ fibril formation. Left: nucleated polymerization at low Aβ concentrations. Right: nucleated conformational conversion at high Aβ concentrations. The latter mechanism is considered to be more related to the progression of AD because it produces a large amount of oligomers, which, together with the fibrils, are cytotoxic.
Other recent studies show that there are differences in Aβ1–42 and Aβ1–40 fibril formation [17]. One of these differences is that the Aβ1–42 fibril has a triple β-motif that consists of three β-sheets (β1: 12–18; β2: 24–33; β3: 36–40); thus, this structure differs from the proposed β-loop-β motif structure for Aβ1–40 fibrils. Additionally, the reported structure of Aβ1–42 fibrils differs from that of Aβ1–40 fibrils from the brain, which have a U-shaped topology with Asp 23-Lys 28 forming a salt bridge and fewer β-regions [18]. Furthermore, in Aβ1–42 fibrils a salt bridge between Lys28 and the carboxylate of the C-terminal alanine (Ala42) was identified; this is important because it shows that Ala42 and not Asp 23, as had been proposed, stabilizes the salt-bridge interaction.
\nAlthough several models of Aβ1–42 fibrils have been described, to date no Aβ1–42 fibril structure has been obtained from the brain, and all that is known about the conformational structure of Aβ1–42 fibrils has been obtained from synthetic Aβ1–42. Therefore, all Aβ1–42 models and observations are approximations that should be accepted with caution because Aβ1–42 fibril formation may be influenced by temperature, pH, and other biochemical parameters that are not considered when the fibrils are formed
As mentioned previously, the mechanism of Aβ1–42 aggregation that has been proposed to contribute principally to the pathogenesis of AD is nucleated conformational change due to the formation of oligomers of Aβ1–42 [20]. When the amyloid hypothesis was first proposed, it was postulated that only Aβ1–42 fibrils were the toxic form of Aβ; however, it is now known that both oligomers and protofibrils are toxic species and that oligomers are more toxic than fibrils [21]. This has been generally accepted due to the finding that cognitive deficits are better correlated with the amount of soluble Aβ than with the number of amyloid plaques; thus, neurodegeneration is not a consequence of amyloid deposition [22]. This is consistent with the oxidative damage produced by the Aβ1–42 oligomers. There are several hypotheses related to Aβ1–42 aggregation and ROS production during AD development and progression. The results of a number of studies support the hypothesis that Aβ1–42 genesis depends on ROS production, whereas other reports suggest that Aβ1–42 is capable of forming ROS [23]. In addition, some previous evidence clearly shows an association between AD and the ROS produced by Aβ1–42 oligomers and metals (Figure 1). Hence, some studies have focused on searching for strategies to avoid the oligomerization of Aβ1–42 by inhibiting it or by decreasing ROS production through the design of multi-targeted compounds; this has resulted in a promising approach [8]. By targeting at this molecular level, it is possible to avoid Aβ1–42 aggregate formation, which functions as a signal that activates microglial cells and initiates an innate immune response that results in the production of high levels of cytokines and ROS.
\nDue to their phagocytic activity, microglial cells represent the macrophages of the brain; for this reason, they are regarded as the predominant immune cells in the brain. In the healthy brain, these cells act as resting microglia, maintaining their ramified morphology and protecting the brain from pathogens by removing them by phagocytosis [24]. However, when microglial cells detect a sign such as a pathogen associated with molecular patterns (PAMPs) or damage associated with molecular patterns (DAMPs), the microglia are activated to acquire a wide range of phenotypes. Two classical phenotypes are the pro-inflammatory M1 phenotype (induced by pro-inflammatory cytokines and/or TLR activation (Toll-like receptor)) and the non-inflammatory M2 phenotype (induced by interleukin (IL)-4), according to the classification for macrophages outside the brain [25]. Aβ1–42 oligomers and fibrils interact with SCARA1, CD36, CD14, a6β1 integrin, CD47, TLR2, TLR4, TLR6, and TLR9 receptors on the microglia; when Aβ1–42 interacts with TLR or CD receptors, the expression of inducible nitric oxide synthase (iNOS), cyclooxygenase 2 (COX2), tumor necrosis factor (TNF)-alpha, IL-1β, IL-6, etc. is induced, resulting in a dysregulated immune response that contributes to neurodegeneration [26].
\nFurthermore, it was found that low concentrations of Aβ1–42 induce microglial proliferation and cause release of H2O2 and O2•− to the extracellular space due to the activation of NADPH oxidase (Figure 3A) [27]. The fact that NADPH oxidase 2 (NOX2) is widely distributed in microglial cells and neurons has been corroborated in
Pro-inflammatory factors produced by the interaction of Aβ1–42 oligomers with TLR or Mac-1 receptors. (A) Aβ1–42 oligomers induce the activation of NADPH oxidase. (B) Production of cytokines induced by the interaction of Aβ1–42 oligomers with the TLR receptor.
It is currently known that unique NADPH oxidase activity is associated with the generation of O2•− or H2O2, depending on the isoform. The confirmation of NADPH oxidase participation in microglial activation and the consequent production of ROS were obtained using cells from patients with chronic granulomatous disease (CGD). Because this disease is characterized by the inability of cells to produce H2O2 due to mutations in the genes that encode the subunits of NADPH oxidase, monocytes and neutrophils from CGD patients fail to produce ROS in response to fibrillary Aβ peptides [31, 32].
\nPark et al. assessed ROS production in the neocortex using hydroethidine fluoromicrography [29]. Fibrillar Aβ superfused through a cranial window increased ROS production in the neocortex. This effect could be abolished by the addition of a peptide inhibitor of the gp91phox subunit. These authors further demonstrated that ROS levels were increased in the Tg2576 mouse model of AD; however, no signs of ROS production were evident in a mouse model in which Tg2576 mice lacked the gp91phox gene.
\nNOX2 is an oligomeric protein composed of three cytosolic subunits (p60phox, p47phox, and p40phox) and two transmembrane subunits (p91phox and p22phox). For the production of O2•− by NOX2, p22phox must form a complex with p47phox. It has been demonstrated that, in primary microglial cells and monocytes exposed to fibrillar Aβ, p47phox and p67phox subunits are translocated from the cytosol to the membrane, favoring the enhanced activity of NADPH oxidase [33].
\nThe production of O2•− together with the neurotoxic factors PGE2, IL-β1, TNF-alpha, H2O2, nitric oxide (NO), and peroxynitrite (ONOO−) can result in neuronal death [34]. Subsequently, the O2•− produced by NOX2 reacts with NO generated by iNOS to form ONOO−. In the presence of excessive amounts of NO, nitration and S-nitrosylation of several proteins, as well as dityrosine formation, occur. Tyrosine 10 of Aβ can undergo nitration, which in turn increases the probability of Aβ aggregation; this is shown by the fact that Aβ nitrotyrosine has been found in amyloid plaques [35].
\nDuring chronic neuroinflammation, microglia maintain the transcription of mRNAs coding for pro-inflammatory factors such as NOX2, iNOS, TNF-alpha, IL-1β, and COX2. The interaction between Aβ1–42 oligomers and TLR receptors begins the phase of neurodegeneration (Figure 3B); as neuroinflammation progresses, the interaction between Aβ1–42 oligomers and Mac-1 receptors results in the production of large amounts of FRs such as O2•−, which is converted to H2O2 to maintain the neuroinflammation (Figure 3A).
\nO2•− dismutates spontaneously or by an enzymatic reaction catalyzed by superoxide dismutase (SOD), an enzyme that can scavenge O2•− and convert it into H2O2 [36]. Because O2•− is the primary ROS produced during the neuroinflammatory process, this is considered to play a key role in the activation of microglia and the activation of NADPH oxidase. However, O2•− can also be produced by xanthine oxidase and during mitochondrial respiration. The O2•− can reduce and liberate ferric ion (Fe3+) from ferritin or ferrous ion (Fe2+) from iron-sulfur clusters. This reaction is of great importance because Fe2+ participates in the Fenton reaction and produces •OH. O2•− contributes to the Fenton reaction via the Haber-Weiss reaction, in which O2•− reduces Fe3+ produced in the Fenton reaction to Fe2+ and maintains iron (II), thereby facilitating the Fenton reaction. The net Haber-Weiss reaction is as follows (1‐3):
Numerous experimental studies have shown that Aβ oligomers are more toxic than Aβ fibrils, and that ROS are produced from the beginning of AD, playing a crucial role in neuroinflammation.
\nIt is well known that certain transition metals are essential for neural function. The levels and transport of these metals are strictly regulated by the blood-brain barrier (BBB), and disruption of metal homeostasis in the brain is thought to play an important role in the pathogenesis of AD [37]. The principal areas of the brain in which metals tend to accumulate are the hippocampus, the amygdala, and the cerebrospinal fluid (CSF); in some of these areas, both senile plaques and neurofibrillary tangles are found (Table 1).
\nThe mammalian brain contains an intrinsically high concentration of copper (Cu2+), zinc (Zn2+), and iron (Fe2+) ions compared to other tissues due to its high requirement for numerous metal-dependent enzymes and metal-dependent metabolic processes [38]. Not only has dyshomeostasis of Cu2+, Zn2+, and Fe2+ been linked with AD but it has also been reported that senile plaques are related to high concentrations of these metals as well as of chrome (Cr3+) and cadmium (Cd2+) (Table 1) [39–41]. Furthermore, these metals are involved in FR production by their participation in the Fenton and Fenton-like reactions; importantly, it has been suggested that they may interact with biomolecules implicated in AD such as Aβ, AChE, and ACh [1], with deleterious results.
\nTo clarify the functions and toxicities of various metals and their relationship to AD, specific information on each metal is provided as follows:
\nMetal and concentration in AD brains (µM) | \nPhysiological functions in the brain | \nBrain areas where metal is accumulated | \nRelationship with AD | \n
---|---|---|---|
Fe2+, 669, 694 | \nFormation and maintenance of the neuronal network and neurotransmitter synthesis. | \nHippocampus (wet tissue), amygdala | \nGeneration of an excess of reactive radical species leading to cell and tissue damage. | \n
Cu2+, 57.7, 53.2, 10–100 | \nCofactor and structural component of enzymes. Regulate synaptic function myelination, synaptogenesis, and synaptic plasticity. | \nHippocampus (wet tissue), amygdala, cerebrospinal fluid | \nCopper in redox-active can catalyze the production of hydroxyl radicals (•OH) in a Fenton-like reaction. May influence clearance of Aβ from the brain at the level of the interface between the blood and cerebrovasculature in AD. | \n
Zn2+, 1000, 300 | \nIt is released from presynaptic nerve terminals into the synaptic cleft upon neuronal activation and has been shown to inhibit excitatory NMDA receptors. | \nAmyloid plaques, synaptic cleft (during neurotransmission) | \nAggregation of the Aβ peptides to form oligomers and fibrils can be rapidly induced in the presence of zinc ions. | \n
Cr3+, 0.3, 0.4, 6.6 | \nCarbohydrate metabolism and normal insulin sensitivity. Brain insulin signal transduction system. | \nHippocampus (wet tissue), amygdala, cerebrospinal fluid | \nReduction of the neuronal glucose and energy metabolism. | \n
Cd2+, 0.25–250, 50–500 | \nIt has not demonstrated a function of brain metabolism. | \nParenchyma, cortical neurons | \nIncrease of the blood-brain barrier permeability and oxidative damage. | \n
Principal metals involved in the development and progression of AD.
Physiological functions, concentrations, brain areas of accumulation, and their relationship to AD.
The diet is the principal source of Cu2+; in fact, studies by Sparks et al. show that the administration of trace amounts of this metal in drinking water may drive the accumulation of Aβ levels in the brain by altering the level of the interface between the blood and the cerebrovasculature in an AD rabbit model [46]. This suggests that dietary metals may promote Aβ accumulation [47].
\nSenile plaques are composed primarily of extraneuronal-aggregated Aβ, microglia, degenerated neurons, and relatively high amounts of redox-active metals such as Cu2+, Fe2+, and Zn2+. Accurate determination of the redox potentials of Aβ and its metal complexes will certainly help unravel their roles in oxidative stress, metal homeostasis, detoxification, and Aβ aggregation/fibril formation. For these reasons, a number of techniques have been employed to determine the amino acids involved in the recognition of metals by Aβ. It is generally accepted that metal ions are bound to the histidine residues at positions 6, 13, and 14 [56]. Several studies have demonstrated that the interaction of Cu2+, Zn2+, Fe3+, and Al3+ with Aβ is maintained by their coordination with His13-His14 of the peptide. The interaction is also maintained by a fourth element represented by a donor atom that can come from the aspartate at position 1 or the tyrosine at position 10, thus forming a tetragonal complex. In fact, marked inhibition of cortical amyloid accumulation by DP-109, a lipophilic metal chelator, has been shown [57].
\nAn important aspect of the binding of Cu2+ to Aβ is that the complex retains its redox activity and is able to produce H2O2. As the principal ROS in living organisms, H2O2 acts as a second messenger in cellular signal transduction under physiological conditions. However, the overproduction of H2O2 results in the formation of high levels of •OH and consequent oxidation of the peptide, which can be detected by the formation of carbonyl groups. It was demonstrated that this oxidation increases as the Cu2+:peptide ratio increases and that it is accompanied by changes in the morphology of the aggregates as determined by AFM [58].
\nIt has been shown that the coordination of Zn2+ with His13 of Aβ is critical to the metal ion-induced aggregation of Aβ [59]. NMR and circular dichroism (CD) studies of metal-Aβ complexes show that Zn2+ binding is dominated by intermolecular coordination and by the formation of polymeric species, including monomeric Zn2+-Aβ and various Zn2+-Aβ oligomeric complexes and aggregates. However, Zn2+-Aβ complex formation is high only in brain areas containing synapses. There, the initial binding of Zn2+ to Aβ induces transformation of the peptide to an oligomeric or polymeric complex with increased Zn2+-binding affinity, potentiating the effect of the metal on Aβ and possibly enabling Zn2+ to act as a seeding factor in amyloid plaque formation [60]. When aggregates are prepared with Cu2+ and Zn2+ ions, the ratio of Cu2+:Zn2+ becomes an important factor in H2O2 generation, the formation of carbonyl groups in the peptide, and aggregate morphology. In fact, Aβ fibrils can hydrolyze H2O2 and generate damage by •OH production [61].
\nFe2+ is able to bind to Aβ, and increased amounts of redox-active iron that can generate an elevated amount of ROS have been found in the brains of AD patients; however, it is not clear how this redox-active Fe2+ is produced. It was postulated that Aβ may act by binding the Fe3+ and reducing it to pathological Fe2+ that is capable of inducing oxidative stress; this would suggest that Aβ possesses a strong reducing capacity for iron and that it acts as a metalloprotein capable of binding the metal ion. The interactions between iron and Aβ are governed by histidines 6, 13, and 14. These amino acid residues could coordinate a shared metal ion and generate a redox-active complex. An alternative explanation might be that an oxidative reaction that uses histidine as a substrate occurs in the presence of Aβ, thereby generating toxic oxygen species [62]. The contribution of each histidine residue to Aβ oligomerization and toxicity is different; it is thought that the His6 residue is important for beginning the Aβ dimerization process and that His13 and His14 are not. However, the latter residues could be important in producing the peptide conformations responsible for the Aβ-iron effects [63].
\nThe reduction of metals (principally Cu2+) by Aβ causes the oxidation of Met35, resulting in the production of H2O2 [64]. In addition, during the catalytic production of H2O2 by Aβ1–42 and Cu2+, the participation of Tyr10 is important because when this amino acid is substituted by alanine (Y10A) there is a significant decrease in the ability of Aβ to reduce Cu2+. Here, it is important to note that the reduction of the metal and H2O2 production allow the formation of the •OH radical by a Fenton-like reaction.
\nAll the available evidence indicates that the Fenton reaction is important during Aβ aggregation and during metal dyshomeostasis in AD. This reaction was first described by H.J.H. Fenton as the strong oxidation effect of Fe2+-H2O2 mixtures on organic compounds in a work entitled “Oxidation of tartaric acid in the presence of iron” [65]. Currently, the combination of Fe2+-H2O2 is known as Fenton chemistry, the Fenton reaction, or Fenton reagent.
\nThe Fenton reaction can be written as follows (4):
During AD, the Fenton reaction occurs due to the presence of excessive levels of active redox metals and the generation of H2O2 by the reaction of Aβ1–42 with the metals. Subsequently, •OH are formed by the interaction of Aβ1–42 and Fe3+ or Cu2+. Several years ago, a speculative mechanism was proposed by which Aβ interaction with metals could produce ROS. In that mechanism, the binding of the metal is followed by the binding of oxygen to the metal via a peroxo bridge and O2•− production; the O2•− are then converted to H2O2, which reacts with metals and produces •OH [66].
\nFurthermore, it has been proposed that during the Fenton reaction an intermediate such as ferryl ion [Fe(IV)=O]2+, a highly reactive oxidant that is able to undergo a reaction involving single-electron hydrogen abstraction and two-electron oxidation, is formed; however, this intermediate is not produced during Aβ1–42 aggregation because it is formed during the reaction of Fe2+ complexes with H2O2 in the presence of organic substrates and a porphyrin complex. Therefore, •OH are produced when aggregated Aβ1–42 interacts with metals. However, several
The Fenton reaction can also occur in the presence of other metals via a Fenton reaction or a Fenton like-reaction, as shown below (7):
where M is the metal (such as copper, which can also be reduced by Aβ1–42) that is oxidized in the reaction. When M = Fe2+, the reaction above is known as Fenton reaction; when M = any other metal, the reaction is known as Fenton-like reaction.
\nIn AD, it has been suggested that •OH formation damages biomolecules such as lipids, proteins, and nucleic acids due to the ability of •OH to catalyze reactions such as hydrogen abstraction, addition reactions, and oxidation reactions. Hydrogen abstraction is one of the most important mechanisms because in this reaction the •OH damages lipids in the brain and, as was mentioned previously, the brain has a high content of lipids. Lipoperoxidation (LPO) is the process by which •OH abstract hydrogen from unsaturated fatty acids, forming alkyl radicals. The principal products of LPO are aldehydes as malondialdehyde (MDA) and propanal, hexanal and 4-hydroxynonenal (4-HNE). LPO of oleic acid in the brain occurs by abstraction of the hydrogens in the ninth and tenth positions; secondary reactions include hydrogen abstraction by alkoxy radicals (RO•) and peroxyl radicals (ROO•) at the tertiary carbon atoms. Then, alkyl radicals (R•) and ROO• are produced by ROS.
\nThe brain is particularly vulnerable to oxidative stress because of its high metabolic rate, which utilizes 20% of the body’s basal oxygen consumption. In addition, the brain has limited antioxidant defenses compared with other organs and high levels of transition metals, principally redox-active Cu2+ and Fe2+; defective regulation of the levels of these metals can lead to reaction with O2 and the production of ROS, resulting in cellular toxicity. Neurons are vulnerable to attack by FRs due to their lower glutathione content in comparison with other cells, their high proportion of polyunsaturated fatty acids susceptible to oxidation, and the fact that their metabolism requires substantial quantities of oxygen. The oxidation of biomolecules such as proteins, lipids, and DNA, and mitochondrial damage have consequences that are deleterious to neurons, including the loss of cell potential, the accumulation of excitotoxic glutamate, decreased glucose availability, decreased intracellular communication, and increased neurotoxicity [68].
\nA large number of biological sources are thought to play important roles in FR production in AD. As mentioned above, some transition metals are increased in AD brains and are present in a redox-active state [69]. Fe2+ catalyzes the formation of •OH from H2O2 by the Fenton reaction in the brains of patients with AD due to the imbalance in metal concentrations, and together with the H2O2 produced by Aβ aggregation it is possible to generate •OH, which results in the oxidation of lipids, proteins, and DNA [70]. Recent histochemical studies have demonstrated that the detection of redox activity in AD lesions is inhibited by prior exposure of tissue sections to Fe2+- and Cu2+-selective chelators. The activity can be reinstated following reexposure of the chelator-treated sections to either copper or iron salts, suggesting that the redox imbalance in AD is dependent on these metals. It is probable that the accumulation of Fe2+ and Cu2+ is a major source of the production of reactive oxygen, which is in turn responsible not only for the numerous oxidative stress markers that appear on senile plaques but also for the more global oxidative stress parameters observed in AD [71].
\nActivated microglia, such as those that surround most senile plaques [72] are a source of the reactive nitrogen species (RNS) NO and the ROS O2•−, which can react to form ONOO−, leaving nitrotyrosine as an identifiable marker [73], as shown in Figure 4.
\nROS and RNS produced after the activation of microglial cells by Aβ1–42. ROS have effects on biomolecules such as lipids, proteins, and nucleic acids.
Several studies have reported that pro-inflammatory molecules and ROS secreted from fibrillar Aβ-stimulated microglia lead to neuronal apoptosis [74]. In addition, neurons, microglia, and astrocytes are capable of generating substantial amounts of NO through the iNOS [75]. Fibrillar Aβ peptides stimulate iNOS and NO production through the NADPH-dependent oxidative deamination of L-arginine [76]. Microglial/neuronal coculture studies reveal that the NO released from Aβ-stimulated microglia causes neuronal cell death. In addition, iNOS has been reported to act synergistically to kill neurons through the formation of ONOO−. This RNS is a potent oxidant with biological reactivity similar to that of •OH. ONOO- promotes the tyrosine nitration and nitrosylation of cysteines within cellular proteins. The addition of nitrite (NO2−) to tyrosine residues is extremely detrimental because it leads to protein and enzyme dysfunction and the eventual death of cultured neurons [77]. Taken together, these data suggest that Aβ-stimulated production of ONOO− plays an important role in the pathogenesis of oxidative damage in the AD brain.
\nThe damage to lipids caused by FRs is evidenced by LPO, which has been demonstrated widely in all areas of the brain and shown to be higher in the hippocampus, the piriform cortex, the frontal lobe, and the occipital cortex [78]. Furthermore, LPO markers have been found in the cerebrospinal fluid (CSF) and urine of patients with AD, and their levels tend to increase with the progression of the disease [79]. Analysis of transgenic mice (Tg2576) that display oxidative damage similar to that found in the brains of AD patients revealed an elevation in oxidative stress markers preceding amyloid formation and increasing amyloid pathology [80]. Data from humans and transgenic mice indicate that elevated oxidative stress is an early event in AD pathogenesis.
\nAdvanced glycation end products (AGEs) are involved in AD through several mechanisms. AGEs, which are produced by the interaction of carbohydrates and proteins, stimulate the production of ROS in the presence of transition metals by the establishment of redox cycling. In addition, both Aβ and AGEs activate receptors such as the receptor for advanced glycation end products (RAGEs) and the class A scavenger receptor and thereby increase ROS production [81].
\nProteins damaged by ROS can be measured in plasma, serum, CSF, and brain tissue. Studies by Smith et al. have demonstrated an increase in the products of protein oxidation in the hippocampus of patients with AD, which showed neurodegenerative changes in comparison with normal and aged subjects [82].
\nThe production of ROS through peptidyl radicals associated with Aβ contributes to Aβ aggregation; it was demonstrated that protein oxidation promotes the formation of protein aggregates. In addition, Aβ causes alterations in several transmembrane proteins present in neurons and glial cells, including ATPases, glutamate transporters, glucose transporters and guanosine triphosphate (GTP)-coupled transmembrane-signaling proteins, resulting in multiple changes in cellular physiology [83].
\nThe type of damage found in macromolecules such as lipids, proteins, and carbohydrates in patients with AD has also been observed in DNA. Mecoccin et al. showed a 10-fold increase in the oxidation of mitochondria and nuclear DNA in brain samples from AD patients [84].
\nThe formation of ROS by any of several possible mechanisms results in damage to neurons. The cholinergic system is the principal neurotransmission system that is affected by the production of oxidative stress. It was postulated that •OH may decrease the activity of AChE by modifying the amino acid residues, which form the anionic site that recognizes the natural substrate, ACh [85].
\nA large body of evidence implicates compromised antioxidant defense systems as a contributing factor in AD pathogenesis; however, studies of antioxidant enzymes in AD have not shown a consistent pattern. Glutathione (c-glutamyl-cysteinyl-glycine; GSH) is an abundant cellular antioxidant. Thiol-reduced GSH normally accounts for the majority (>98%) of total cellular glutathione, but it can also exist as oxidized glutathione disulfide (GSSG) or glutathione adducts. Glutathione peroxidase (GPx) catalyzes the oxidation of GSH to GSSG, whereas the reverse reaction is carried out by glutathione reductase (GR), which requires NADPH. Coupled to the oxidation of GSH, GPx can reduce H2O2, highlighting the importance of both GPx and GR in maintaining the cellular redox state. Indeed, the measurement of erythrocyte levels of GSH, expressed as the ratio of GSH/GSSG, provides a dynamic marker of oxidative stress
As previously mentioned, the production of high levels of ROS is related to the establishment and progression of AD. Among these ROS are O2•−, H2O2, •OH, NO, and ONOO−, which can be produced by several mechanisms (direct ROS production by Aβ1–42 oligomers, interaction of Aβ with metals, microglial activation, etc.). For these reasons, a variety of techniques have been employed to determine the species and amounts of ROS in biological samples of patients with AD and in samples from animal models.
\nAmong ROS, O2•− and •OH are molecules with unpaired electrons that react rapidly with various biomolecules. To quantify these molecules by electron paramagnetic resonance (EPR), it is necessary to employ compounds that increase the half-lives of the unpaired electrons. The most common compounds employed for this purpose are 5,5-dimethyl-1-pyrroline
Although the EPR technique is of great help in identifying and quantifying FRs, its use is limited due to the fact that it requires an EPR spectrometer, which is expensive. If an EPR is not available, other techniques can be used to determine the amount of ROS produced; however, one disadvantage of these techniques is that they require samples from animals that must therefore be sacrificed.
\nThere are several techniques that permit the quantification of O2•− in biological samples; these include cytochrome C, WST-1 [2-(4-iodophenyl)-3-(4-nitrophenyl-5-(2,4-disulfophenyl)-2H-tetrazolium monosodium salt], lucigenin, luminol, and others. Several of these techniques are described below.
\nReactions for the determination of O2•− and H2O2. (A) Reduction of WST-1 by O2•− to a water-soluble yellow formazan. (B) Reduction of lucigenin by O2•− to a lucigenin cation radical. (C) Oxidation of luminol by H2O2. (D) Oxidation of Amplex red by H2O2 in the presence of HRP to produce resorufin.
To determine the amount of H2O2, electrodes can be used, and the amount of H2O2 can then be determined polarigraphically. The sensitivity of the electrode allows precise and rapid measurement of extracellular H2O2. Other probes include the use of targets and are based on the ability of H2O2 to oxidize molecules such as Amplex red (N-acetyl-3,7-dihydroxyphenoxazine), scopoletin, and homovanillic acid in the presence of HRP. There are also many other techniques that allow the determination of the amount of H2O2, such as aryl-borate-based probes, peroxy Lucifer, and others; however, Amplex red is one of the most used. Amplex red is a non-fluorescent compound that is oxidized by H2O2 in the presence of HRP to produce resorufin, which is colored and highly fluorescent at 587 nm (Figure 5D). Amplex red has been used to measure H2O2 production by microglial cells and also directly
It has been demonstrated that Aβ1–42 is one of the principal biomolecules that contributes to the development and progression of AD due to its ability to generate ROS by its interaction with metals and also due to its ability to activate specific cells, producing neuroinflammation and consequently neurodegeneration. Therefore, therapeutic treatments to avoid Aβ production should be developed by the design of selective inhibitors of the β‐secretase BACE-1.
\nThis research was financially supported by COFAA-SIP/IPN [Project: 20161374; 20161383; 20161399], and CONACYT [Project: CB254600, I010/0532/2014]; [Project: PDCPN782].
\nSince time immemorial, people have steered clear of change because of its complexity and the need to adapt to completely different mindsets. Any kind of change is difficult to accept because it demands that people leave behind the ideas and concepts, they trust and substitute them for something that is new but uncomfortable to them. The question then is not about turning up with something novel, but about persuading people to accept that change. This requires building trust and collaboration, as no change or innovation would be successful without joint action or collusion. The present century is one of adventure, excitement, and many challenges. Financial insecurities, social embarrassments, and a need to jump out of comfort zones are major factors driving a need for change and have decreased the adoption time for people. This has major implications on society because now more than ever, consumers are willing to put a premium on innovation. And innovation is the starting point for a revolution. Thus, it is essential to understand what exactly is meant by innovation?
Before moving on further, let us explore what innovative thinking is. One way it can be defined is as a “potentially powerful influence on organizational performance”. More importantly, to introduce innovation within an organization, there is a need to look for people who believe in something, who are willing to cooperate, and who are passionate. Innovation leadership is thus the ability to inspire productive action in yourself and others during times of creation, invention, uncertainty, ambiguity, and risk [1]. It is a necessary competency for organizations that hope to develop truly innovative products and services [2]. Often, innovation is confused with invention and the generation of new ideas. Like invention is the conception of a new product, innovation is about making the existing product function better. Like they teach you in design strategy classes in MBA, the invention is the first boat ever pushed out to sea: it may be profound or fill a significant void in history. However, is it consequential? Can it be easily accessed by people in day-to-day life? Even though a prodigious new discovery in a lab might be a wonderful invention, yet if it does not create value in the market, if people do not trust it, it is not an innovation. Coming up with advanced tech products every year to gain profit is of no use if its usefulness to society is nil. Innovation is thinking out of the box. And how do you know if something you created is of use to someone? How do you stay relevant as an organization? That is where innovation leadership comes into play. Because as they say, “From the idea to the invention, concept to creation…… Execution is the key”.
Ever wanted to augment your creative potential to tackle the escalating technological as well as social challenges that we are facing today? Ever wanted to equip your team or employees to take “leaps of faith “ that would enable them to overcome these complex obstacles and create a better product for society? That is what innovative leaders’ practice. Even though innumerable definitions of innovation leadership exist, still one that explains it all is the fact that innovation leaders help people translate their ideas into reality. Innovation is not just doing something new for the sake of it, but to add value or solve a problem within an existing system or organization. George Cuoros defines innovation as a way of thinking to create new and better things. Innovation can result from either “invention” (all new) or “repetition” (change of what already exists), but if it does not correspond to the idea of “new and better”, it is not innovative [3].
The words that come to your mind when you hear about the word “leadership” include mentor, vision, support, manager, ethics, influence, etc. “A leader is someone who builds their team, mentors them, and then advocates for them,” [4]. What then is meant by innovation in leadership? Innovation leadership involves synthesizing different leadership styles in organizations to influence employees to produce creative ideas, products, services, and solutions. These innovators who use their creative capacity enough to advance, help us to make big strides and lead us to a new age of betterment. One of the things that every great innovator has is that not one of them accepts the status quo. Innovative leaders cultivate an environment where ideas can be developed, and better yet where they can blossom. They are visionaries who lead by example and more importantly foster collaboration, creating a culture of trust and venturousness where those under them are not afraid of trying out new ideas, as they know the leader has their back. In his memoir, “The Long Walk to Freedom,” Nelson Mandela compared the roles of leader and shepherd as follows: “I piloted from behind.” [5]. Innovation leaders basically commit to making organizations work for the greater good and innovation leadership takes its inspiration from a vast array of sources. This chapter will explore the various theories that have dictated innovation leaders over the years, how creativity begets conception of new ideas, look at case studies to understand strategies that have helped in the evolution of certain companies, and sum it all up with the best practices that should be promoted to create innovative leaders.
We believe innovation leadership provides particularly powerful lessons to those wanting to address the big challenges of developmental reforms within their organizations. We can define leadership as the ability to influence a group towards the achievement of its goals. In management terms, if you achieve the aim of an organization, through its members by the use of your authority, then that is called leadership. There are various theories prevalent today that dictate how leadership should look like. It is essential to really understand these theories to meet our organizational goals and groom leaders within organizations.
This theory has been around since 1970 when Martin Evans developed it while Robert House improved it in 1971. The Path-Goal model emphasizes the importance of the leader’s ability to interpret followers’ needs accurately and to respond flexibly to the requirements of a situation [6].
The basic argument that this theory offers is that it is the chief responsibility of the leader to motivate the followers to conclude their tasks, and the leader does that by removing any obstacles in their path. To reiterate it, if the followers are motivated enough to attain a sense of fulfillment after they accomplish a task, and if all the negating factors in their way get cleared, they could take these tasks to completion. In the most simplistic terms, Path-Goal theory is about “how leaders motivate their followers to accomplish goals” [7].
Why is it called the Path-Goal Theory? Because it emphasizes the fact that leaders should change their leadership styles to their subordinates or adopt a path based on the situations, they face to achieve a goal. It is molded on the Expectancy Theory of Motivation. Breaking it down for the layman, when will your employees or your team be motivated enough to work towards a task? First, when they believe that the goals, they have received are attainable (Expectancy). Second, when there is a promise of a reward (Instrumentality). And third, if that reward holds any value for them (Valence).
Therefore, in the Path-Goal theory, leaders go about looking for ways to motivate their teams to achieve their objectives, eliminate any roadblocks or ambiguities in their way and make sure that the fruit these efforts bear is desirable. It is similar to the way a parent removes obstacles from a child’s path so that he can attain excellence in the best environment possible.
Now, depending on the situation a leader faces and the kind of employee or teammate he has under him, there are four kinds of behaviors that he may need to adapt to increase productivity and thus the possibility of innovation within his organization. It would also improve job satisfaction and performance. According to (House and Mitchell 1974, p. 83), this approach has focused on “directive, supportive, participative, and achievement-oriented leadership behaviors” [8].
Directive- Like old-fashioned management, this includes planning, organizing, specifying standard protocols, or making policies based on the task.
Supportive- When there is a warm and friendly surrounding, it enables open communication between team members and the leader.
Participative- Like one-on-one peer sessions in classrooms, this behavior style asks for inputs from subordinates, enables an open discussion between them, and juggles ideas in a way that each member has an active involvement in the decision-making process.
Achievement-oriented- A style where the main focus is on the attainment of the goal.
Thus Path-Goal theory is instrumental in dictating the responsibility that a leader has towards the organization and the users [9]. But how do leaders then decide which style to follow?
For example, if your followers have known how to approach a situation and are skilled, but they are not confident about their approach, then in this state you adopt a participative style, engage in an open discussion with them, get them to talk, discuss ideas and guide them on a clear path.
On the other hand, if your followers are unskilled, not in control of the situation, completely naive, then it’s time to adapt the directive leadership style. Apple’s culture of fairness to the employee was nurtured by Steve Jobs. As the leader, he adopted the participative style and understood that he needed to work with highly motivated employees. He did not only act as a leader but he offered guidance to the employees giving them a sense of direction [10].
The Leader–Member Exchange (LMX) literature is hardly at its infancy, but the field is still under progressive development [11]. This theory suggests that leaders automatically develop a relationship with each of their subordinates, and the strength of these relationships strongly influences the productivity within the organization. It encompasses two-way communication between the leader and the team member. The more trust, loyalty, and support present in this bond, the better the performance of the team members will be.
A study done in 2017 found that this theory fully mediates the relationship between abusive supervision and intrinsic motivation; intrinsic motivation partially mediates the relationship between LMX and creativity, and LMX and intrinsic motivation sequentially mediate the relationship between abusive supervision and individual creativity [12]. There are three stages through which this leader-subordinate relation passes-
When a team member joins the group and the leader gauges how skilled he is, the manager is still forming an initial assessment of the team member, just like in real life when we meet someone new for the first time. This stage is called Role Taking.
Based on his assessment of the team, he will divide them into two groups, one that forms his inner circle i.e., people close to him who proved their loyalty or trust. And another group is the outer circle, which has not formed as strong bonds as the inner group. This stage is called Role Making
They based this theory on the assumption that each individual is different and thus has different communication needs. Or in other words, that every member of the team is unique and must be treated differently. The findings of a study published in the International Journal of Organizational Leadership demonstrated that there exists a significant and positive relationship between LMX and organizational change management [13].
A proper understanding of these theories thus helps foster the right environment for innovation by providing a general direction on necessary leadership functions.
And innovation climate (top management support, resource supply) mediates the relationship between transformational leadership and organizational innovation because effective leadership should build a supportive climate for innovation [14]. Organizational innovation is the implementation of a method that has not been used before in the organization, it results from the strategic decision that management has taken [15].
Now that we clearly understand innovation, leadership, and the roots behind these concepts, let us ponder on the significance of “creativity” for promoting innovation.
Although almost identical on face value, creativity and innovation hold different connotations in real life. While every innovation involves creativity, not all forms of creativity lead to innovation. And understanding the clear distinction between these ideas helps leaders flourish in their organizations. One of my favorite analogies to make this easier to understand is the invention of pasta. Creativity involves coming up with an entirely new dish or recipe of the Italian pasta. Whereas innovation is modifying what is already known about pasta to make it more appealing to the market. Like changing the shape of the pasta, or making it more colorful to attract children.
It is safe to assume that there is truly a connection between creativity, leadership, and innovation? The use of Apple products has been rampant in the past few decades, and iPhone has emerged as one of the greatest inventions in recent years, especially among youth. He was a man who did not accept conventional wisdom about cell phones that existed and challenged it. He did not respect it and struggled to work around ways of turning that invention into innovation through his creative ideas. When thinking about tablets, smartphones, and laptops, it’s almost inevitable that Apple and its companion Steve Jobs will appear. But instead of seeing Jobs as the inventor, it’s better to see him differently because Walter Isaacson’s biography calls him a “tweeker.” [16, 17]. His creative flair led him to go out of his comfort zone, challenge the existing deficiencies and lead to the creation of a new innovative product.
Rajendra Prasad, who is a common name in the field of fashion and architecture, believes that the gap between being a fashion symbol and taking the entire fashion industry by storm lies in the realm of creativity. It lies in the ability of ordinary people to do extraordinary things and lies in the minds of the out-of-the-box thinkers who take the first courageous leap into the unknown and bring back something spectacular. These people are nothing short of leaders, who, through their creative mindsets, give birth to amazing innovations. In the process of creative entrepreneurship, apart from using creativity to build a business, these entrepreneurs also need to strike a balance between creative ideas, creativity, and entrepreneurship, which is achieved through the management and leadership behavior of creative entrepreneurs [18]. A creative leader hears something in one place, hears something else in another place, and somehow assembles it to come up with an innovation. That is how creativity, leadership, and innovation gel so well together.
To sum it up, creativity leads to innovation, and innovation gives birth to leadership. There is a basic formula to becoming a leader or starting entrepreneurship. It is a function of two major things- an initial idea and a willingness and creativity to engage in and sell that idea. Also, heroic creativity and leadership feature strongly in the careers of creative workers, optimizing well-being, satisfaction, and career coping strategies.
Having come to this point in the discussion, let us rewind to what we started this discussion with. The notion that it is the people and their cooperation that leads to the best kinds of innovations. Combine that with a creative mindset and the right direction, and you get innovative leaders to lead the team forward. Ever then wondered why some companies or organizations succeed at doing this while others fail. From research over countless years and by many researchers, it all boils down to having the right strategy. And not only that but also being able to implement that strategy.
Many models of promoting innovation leadership in organizations have come into play in recent times. There are varied opinions regarding the same. Some belief in implementing an innovation culture by motivating your teammates to seek advancement. But this wastes resources and is based on a dependence on skillful people who can leave the team anytime. Another model that some companies use is of hiring what they call an “inventor” or innovation consultant, who propose ideas that are then taken to realization. This again means relying on external sources for the successful leadership of your organization. To give a better frame of reference, some corporations use mixed tactics that include open and closed innovation approaches.
The most important question to ask for the leaders while devising an appropriate strategy is related to their expectations from their organization and themselves in the future. How do they want to reinvent their team? Is the plan of action they have aligned with their goals for the company? If yes, a strategic model for innovation leadership is then nothing more than a roadmap for a team’s coveted future. Strategic innovation takes the road less traveled – it challenges an organization to look beyond its established business boundaries and mental models and to participate in an open-minded, creative exploration of the realm of possibilities [19, 20].
Here, I will give you a basic structure on how organizations should choose the best strategy. First of all, start with making sure you are selecting the leadership styles or practices that you are more equipped to execute than your counterparts. One relatively solid framework for making those strategic choices and choosing those behaviors is the strategy choice cascade [21]. It is described in the strategy book titled Playing to Win by. Former P & G CEO Lafley and Roger L. Martin, Dean of the Rotman School of Management at the University of Toronto.
One of AG Lafley’s specific suggestions is that organizations build and develop an entire list of strategic decision-makers who know what it takes to attract and connect with participation and a more conscious structure. Innovation is one of the most difficult to align with strategy. It’s chaotic in nature, and its team-oriented approach sometimes pushes the boundaries, challenging a variety of established positions and becoming seemingly contradictory. Achieving alignment requires some better options that repeatedly trace back to innovation activities and strategic needs [22].
This requires a selection cascade model. In this model, understanding flows through coordinated cascade decisions. Its purpose is first to give the “decision-maker” the opportunity to make individual decisions so that they can move it upstream again by stimulating and facilitating different levels of common sense or best judgment. Roger Martin and Hillary Clinton proposed “the art of integrated thinking [23]. To sum it all up, just as in battles, businesses or governments, similarly a good strategy put to work is what separates a successful innovation leadership from a poor one. This makes strategic leadership one of the most important components of innovation in the 21st century.
The days of brainstorming on whiteboards and sticky notes are long gone. Innovation in leadership looks slightly different in this century, especially when we talk about digitalization. But what exactly is digital transformation? “It is the integration of digital technology into all areas of a business, fundamentally changing how you operate and deliver value to the customer “. This transformation has also come about as a cultural change that requires companies to constantly challenge the present state of affairs, and observe and gracefully accept failure. Since users are now at the center of every digital experience, it has now become all the more important to develop leaders that cultivate a work culture that rewards innovation which in turn drives efficiency and thus better delivery of services to the users. Rapid growth in mobile connectivity and remarkable strides in the cloud has reduced the costs incurred in establishing global platforms since it has become simpler to dismantle technological barriers. In fact, as research by the MIT Sloan School of Management shows, 14 out of the top 30 brands by market capitalization in 2013 were platform-oriented companies. These organizations thrive on digitalization in innovation leadership [24].
Also, businesses are now being measured by the outcomes of the services they deliver which has increased the importance of selling results that appeal to the customer. A rising enterprising culture means that hundreds of start-ups have emerged that have overshadowed the traditional markets that could not keep up with digitalization [25]. Include a list of Uber, Twitch, Tesla, Hired, Clinkle, Beyond Verbal, Vayable, GitHub, WhatsApp, Airbnb, Matternet, Snapchat, Homejoy, Waze, and more. These startups can scale much faster than traditional analog companies. It took 20 years for Fortune 500 company to reach an average market capitalization of $ 1 billion, but Google achieved that in 8 years, and companies such as Uber, Snapchat, and Xiaomi achieved it within 3 years [26]. What is the reason behind this tremendous growth? Maybe because these enterprises have the foundational stability and the 360-degree vision to enter and dominate as-yet unidentified niche markets which will forever remain shut to the slower moving, more traditional stalwarts of the industry.
To put this concept into perspective, as Zeike et al. (2019) mention, we measure the holistic vision of digital leadership as an overlap between digital literacy (i.e., computer literacy, ICT literacy, digital competence, etc.) and digital leadership itself. In simpler terms, leadership capabilities are the ways in which managers are driving change [27].
I will end this on a case study of the leading aerospace company in the world and how it was transformed for the digital age. Boeing is sitting in the gold mine of the data. A single trip on one of the company’s 787 Dreamliners can generate up to 1 terabyte of data. It takes hundreds of planes and tens of thousands of trips a year … well, you understand what’s important. However, to use all this data to improve features such as product development and value-added services for customers, a 102-year-old company needed to redefine its an approach to software [28]. Bill Boeing created the company in 1916 with the clear philosophy “build something better “. Niki Allen, a 14-year veteran of the aerospace company lead the effort to transform Boeing’s approach towards digitalization. To execute this, Allen developed a “master plan” that was based on the Three Es: Engagement, Excellence, and Enablement. Her approach is illuminating to other organizational executives embarking on digital transformation journeys at their enterprises and sheds light on how innovation leadership in a digital world looks like [29].
The radical transformation of 21st century organizations is nothing less than a modern-day industrial revolution wherein innovation now plays a critical role in determining organizational success (Cascio & Aguinis, 2008, 2019). Disney’s animation studio Pixar uses cutting-edge technology and creative collaboration to create a competitive advantage. Pixar movies (Finding Nemo, Finding Dory, Toy Story 3, etc.) are one of the top 50 movies to date, with Toy Story 3 recording $ 1.06 billion in 2010 sales (Mendelson, 2017), as it became the third-highest animated film in history. The secret to Pixar’s success is the founder’s innovation leadership. Edwin Catmull and Alvy Ray Smith inculcated an environment where creative ideas could be turned into innovations by following certain best practices [30].
So how do you become an innovator if you are not already that? Do these innovation leaders follow certain practices or show certain behaviors that make them different from their counterparts? Well yes, they do. To begin with, these leaders create a safe space for innovation by developing an environment that allows for the respectful sharing of ideas. If the subordinates are not afraid of being reprimanded for presenting their thoughts, they would be more open to sharing them. For instance, Toyota encourages innovation by removing some of the pressure for short-term returns. Toyota’s decade-long investment in its Prius sub-brand ultimately succeeded in strengthening the company’s reputation as a respected product innovator while allowing Toyota to capture a first-mover advantage in the fast-growing hybrid category [31]. Secondly, these leaders observe the world like an anthropologist and learn from their setbacks. They are not afraid of pushing their boundaries. An example of an employee’s performance assessment is “productive failure” if an employee tries something and fails, but learns valuable lessons or can adapt from what did not work to what worked [McKinsey Global Institute, 2014]. At Dow Chemical’s risk-taking is not only accepted, it is encouraged, which helps the company to stay agile and innovative. Dow sources said: “Empowerment really helps to stay agile. We encourage you to take the courage to lead and keep asking “what if” and “why?”. We recognize opportunities for our employees and challenge them to push the boundaries.”
Thirdly, innovation leaders are known to be persuasive. They present their ideas with such eloquence that the team is forced to follow them at the drop of a hat. On top of that, they display their vision for the future with excellence and alacrity. Finally, innovation leaders are courageous and trust themselves enough to trust others in the team. They have full faith in their ideology and the expectations they have from their organizations. Along with being courageous, they exhibit intellectual humility which is the ability to listen to others and admit your own mistakes. In a recent op-ed piece, [for example, Thomas Friedman 2014] recounts the five attributes internet giant Google looks for in new employees. They include intellectual humility – an ability to recognize and admit mistakes to others. Gardner recognizes the environment and potential for change in the future and believes that there are five minds that must be cultivated for the success of the 21st century. These five spirits are a disciplined mind, a synthetic mind, a creative mind, a respectful mind, and an ethical mind. Gardner acknowledges that he could have broadened the use of the word mind and perhaps used more accurate perspectives and skills, but the word mind is an individual action, thought, emotion, or action. It reminds me that it is created in my mind. Gardner pays no special attention to any one of these minds, emphasizing that their development is equally important.
According to the Center for Creative Leadership creativity experts David Horth and Dan Buchner, creating an innovative organization “is about growing a culture of innovation, not just hiring a few creative outliers.” This chapter puts into perspective a host of possible ways in which innovative leaders have brought revolutions in the field of entrepreneurship. This chapter draws on the way some companies have achieved spectacular successes through behaviors to promote innovation and creativity. It distinguishes innovation and invention and sheds light on the various theories that have been put forward in recent years. It emphasizes the importance of providing enough autonomy to allow leaders with the development ideas to test innovative solutions in their teams. Innovative leaders have certain behaviors that set them apart from their counterparts and enable them to bring a change in their organizations. Entrepreneurs should be able to balance vision with managerial skill, passion with pragmatism, and proactiveness with patience. They should be able to build a high trust environment that promotes and fosters innovation. The implications of not establishing a high-trust environment among team members are huge because trust is the gateway to candor – the honest and frank exchange of ideas vital for “getting to the best idea”. Professors and Ph.D. students in ecology and evolutionary biology, Iain Couzin and Albert Kao, respectively, have discovered that “popular wisdom” does not always lead to better decisions. Instead, the results of studies of individuals within the group, whether human or other animal species, suggest that small groups maximize decision-making accuracy in many situations. (Kao and Couzin, 2014, cited in Zimmer, 2014).
This chapter also brings to attention the connection between leadership, innovation, and creativity and how it all adds up to bring exponential growth in conglomerates. Innovative leaders like Steve Jobs and A.G Lafley lead by example and show the world how the correct choices in leadership and the perfect alignment of goals could yield massive results. They called it the Cascade of Choices. To put cherry on top, digitalization has made life easier. Although there are still certain ambiguities involved, yet with the crossing of technological barriers, traditional organizations have been left behind and new start-ups are starting to emerge and evolve. Advancement in digital technology has also enabled better access to remote areas and communities which has made it easier to cater to their user demands. As a result, small companies have flourished and gained momentum, which they would not have been able to do earlier. Going forward with the motto of creating something better, innovation leaders have started to evaluate the expectations they have from their teams and organizations and help these direct the course of action they want to take. Boeing is an example of such a conglomerate. In a review of great entrepreneurs like Steve Jobs of Apple, Bill Gates of Microsoft, Jeff Bezos of Amazon, Martha Stewart, Jack Bogle of Vanguard, and Howard Shultz of Starbucks, CNBC’s chief editor Eric Schurenberg (2014) notes “the thread that stands out, partly because it’s unexpected, is a failure. Or more precisely: the ability to absorb failure and – by determination, grit, pugnacity, whatever – turn it into success.” (for example, Myers et al., 2014).
The chapter ends meaningfully on the best practice recommendations that every leader should follow to bring about innovation in his sphere, whether it be through creating a safe culture for his subordinates that promotes discussion or be it through pushing boundaries and challenging the status quo. His team members must be encouraged to show their vulnerabilities, to reveal what they know or think, and to accept their mistakes and willing to correct them. There should be elimination of a hierarchy system that leads to an atmosphere of fear within the organization. Inculcating these practices can bring about positive changes towards innovation.
The authors declare no conflict of interest.
The Internet has irrevocably changed the dynamics of scholarly communication and publishing. Consequently, we find it necessary to indicate, unambiguously, our definition of what we consider to be a published scientific work.
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\\n\\nAlthough such papers are regularly made publicly available via personal websites and institutional repositories, their general purpose is to gather comments and feedback from Authors’ colleagues in order to further improve a manuscript intended for future publication.
\\n\\nWhen submitting their work, Authors are required to disclose the existence of any publicly available earlier drafts in a note to the Academic Editor. In cases where earlier drafts of the submitted version of the manuscript are publicly available, any overlap between the versions will generally not be considered an instance of self-plagiarism.
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\\n\\nWe feel that social media, blogs and message boards are generally used with the same intention as grey literature, to formulate ideas for a manuscript and gather early feedback from like-minded researchers in order to improve a particular piece of work before submitting it for publication. Therefore, we do not consider such internet postings to be publication in the scholarly sense.
\\n\\nNevertheless, Authors are encouraged to disclose the existence of any internet postings in which they outline and describe their research or posted passages of their manuscripts in a note to the Academic Editor. Please note that we will not strictly enforce this request in the same way that we would instructions we consider to be part of our conditions of acceptance for publication. We understand that it may be difficult to keep track of all one’s internet postings in which the researcher´s current work might be mentioned.
\\n\\nIn cases where there is any overlap between the Author´s submitted manuscript and related internet postings, we will generally not consider it to be an instance of self-plagiarism. This also holds true for any co-Author as well.
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\n\nOther than the issue of originality, research misconduct is another major issue that all publishers have to address. IntechOpen’s Retraction & Correction Policy and various publication ethics guidelines identify both redundant publication and (self)plagiarism to fall within the definition of research misconduct, thus constituting grounds for rejection or the issue of a Retraction if the work has already been published.
\n\nIn order to facilitate the tracking of a manuscript’s publishing history and its development from its earliest draft to the manuscript submitted, we encourage Authors to disclose any instances of a manuscript’s prior publication, whether it be through a conference presentation, a newspaper article, a working paper publicly available in a repository or a blog post.
\n\nA note to the Academic Editor containing detailed information about a submitted manuscript’s previous public availability is the preferred means of reporting prior publication. This helps us determine if there are any earlier versions of a manuscript that should be disclosed to our readers or if any of those earlier versions should be cited and listed in a manuscript’s references.
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\n\nNevertheless, Authors are encouraged to disclose the existence of any internet postings in which they outline and describe their research or posted passages of their manuscripts in a note to the Academic Editor. Please note that we will not strictly enforce this request in the same way that we would instructions we consider to be part of our conditions of acceptance for publication. We understand that it may be difficult to keep track of all one’s internet postings in which the researcher´s current work might be mentioned.
\n\nIn cases where there is any overlap between the Author´s submitted manuscript and related internet postings, we will generally not consider it to be an instance of self-plagiarism. This also holds true for any co-Author as well.
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