Open access peer-reviewed chapter

Astrocytic S100B, Blood-Brain Barrier and Neurodegenerative Diseases

Written By

Anuradha Krishnan, Hao Wu and Venkat Venkataraman

Submitted: March 6th, 2019 Reviewed: March 17th, 2020 Published: April 22nd, 2020

DOI: 10.5772/intechopen.92146

Chapter metrics overview

801 Chapter Downloads

View Full Metrics

Abstract

Increased life span and expectations of a better quality of life have resulted in a spotlight on neurodegenerative and cardiovascular diseases generally associated with aging. The drive toward evidence-based medicine has necessitated a constant search for objective biomarkers to assay disease onset, progress, and outcomes to make the best clinical decisions. Enhancement of their use depends on the mechanistic understanding of the biomarker’s role in the disease process itself. This chapter focuses on S100B. It is a calcium sensor protein that is primarily astrocytic. While it plays a complex, interlinked role in signaling, serum levels of S100B as a biomarker for clinical decisions is also an area of intense investigation. Both aspects are presented, with an emphasis on the role of S100B in in maintaining a blood-brain barrier, especially in the context of suggesting a unified mechanism for the onset and progression of neurodegenerative diseases.

Keywords

  • S100B
  • calcium
  • blood-brain barrier
  • biomarker
  • neurodegeneration
  • tight junctions

1. Introduction

Rudolph Virchow first proposed the concept of neuroglia as a component of the connective tissue of the brain “nervekitt” [1]. The term “astrocyte” is attributed to Michael von Lenhosseck, coined to denote the stellate (star-like) morphology, with independent contributions also by Kolliker and Anderiezen (reviewed in [2]). The diversity of this group of cells was brought into clear focus by the excellent drawings by Cajal [3]. Glial cells, including astrocytes, were once believed to be limited to passive support in the functioning of the brain. Work over the last few decades has ushered in the understanding that they actively participate in normal metabolism and physiology of the brain, even more so during injury response and repair. They alter the microenvironment through secretion of a variety of signals including cytokines as a result of intracellular process collectively termed “activation,” which operates at both ends of time scale—acute and short-term (trauma) as well as chronic and long-term (neurodegenerative diseases). While meant to be adaptive and reparative, they could also lead to exacerbation of injury or disease (for some reviews, please see [4, 5, 6, 7, 8, 9, 10, 11, 12]). Understanding the process of activation and its effect on the microenvironment is fundamental to devising positive interventions. One of the important signaling molecules involved in this process is S100B, a calcium sensor protein, which is secreted to act at the extracellular level but also functions intracellularly (reviewed in [13, 14, 15]). While primarily astrocytic, it is expressed in other glial cells, non-neuronal cells, and is also detected in the serum. In this chapter, the role for S100B in the neurovascular unit (NVU)—important for the blood-brain barrier (BBB)—is discussed. A summary of conditions in which the serum S100B levels are proposed to be of values as a biomarker provides the backdrop. Based on the findings, a mechanism that places the NVU, with a central role of S100B, at the heart of neurodegenerative diseases is suggested.

Advertisement

2. S100B: the protein

S100B, an astrocytic protein, was originally obtained from the bovine brain [16], as a mixture with S100A1—the fraction was termed “S100” due to partial solubility in 100% saturated ammonium sulfate solution [16], reviewed in [15]. Over 50 years after the identification of S100B, the S100 family now includes more than 20 genes paralogous to S100B, with functions in healthy as well as diseased states [17]. The S100 proteins exist mostly as dimers—homodimers or heterodimers—and share common structural motifs such as the Ca-binding EF hand.

S100B is a homodimer of a 92-amino acid protein, termed S100b, with a molecular mass of 10,713 Da, but migrates between 9 and 14 kDa on SDS-polyacrylamide gels. Crystal structures and refined NMR structures [18, 19] reveal that the monomer contains two EF-hands—one non-canonical and one conventional—that bind calcium; the dimer is in antiparallel orientation. Upon binding calcium, the molecule switches to a more open conformation with hydrophobic patches exposed to facilitate interaction with other molecules. However, these conformational changes are unlike other more conventional EF-containing proteins and are unique for S100B protein—experimentally supported through calcium-induced mobility shift assays [20]. Thus, the S100B protein is specialized to sense changes in calcium levels and mediate appropriate responses, especially in the nervous system.

Expression of S100B in the nervous system is primarily in the glial cells—astrocytes in the central nervous system and Schwann cells in the peripheral nervous system, where they carry out intracellular as well as extracellular functions [reviewed in [14, 15]]. Since these functions are relevant to both healthy and diseased states and S100B is detectable in serum, specifically humans, a focused effort has been underway to determine if S100B could serve as a biomarker.

Advertisement

3. S100B: the biomarker

Biological marker (biomarker) is defined as “a characteristic that is objectively measured and evaluated as an indicator of normal biologic processes, pathological processes or pharmacological responses to a therapeutic intervention” (Biomarker Definitions Working Group). An optimal biomarker is ideally measurable easily, quantitatively related to the extent of the condition, yields reproducible results, and provides guidance regarding outcomes/clinical decisions [21]. The quest for a biomarker may pass through several avenues that include imaging, functional imaging, microRNAs, and microarrays. Even as these journeys have increased the knowledge base, they have also highlighted the complexity of the process. Typically, however, biomarker levels in body fluids—blood, cerebrospinal fluid, saliva, or urine—are more common.

A summary of current information on the correlation of serum S100B levels to different conditions is provided in Table 1.

ConditionCitationComments
Brain-related
Traumatic brain injury
 Mild[22]
 Moderate[23, 24, 25, 26]Not a reliable predictor of good vs. bad outcome
 Severe[24]Useful to predict if the patient will regain consciousness 3–6 min after injury, in addition to predicting the outcome
 Children[27, 28]Normal serum levels are higher than in adults. Cannot be used as a predictor of injury, but is a predictor of outcome
 Sub-concussive head impacts[29]
 Non-traumatic intracerebral hemorrhage[30, 31]
 Stroke (ischemic and hemorrhagic)[32, 33]
Heart-related
 Cardiopulmonary bypass surgery[34]Meta-analyses
 Congestive heart failure[35]Further increase if accompanied by renal insufficiency
 Dilated cardiomyopathy[36]
Skeleton-related
 Orthopedic trauma[37]
 Hip arthroplasty[38]
Cancer-related
 Brain metastases of lung cancer[39]
 Estrogen receptor-positive breast cancer[40]Elevated levels indicate poor disease-free survival
 Malignant melanoma[41, 42, 43, 44]Elevated levels indicate poor disease outcome
Neonates-related
 Congenital heart disease[45]Levels dropped to normal 7 days post-operative
 Intraventricular hemorrhage, intrauterine growth restrictions, perinatal asphyxia[21]
 Hypoxic ischemic encephalopathy[46]
Other diseases
 Epilepsy[47, 48]
 Delirium[49, 50]
 Neuromyelitis optica (AQP4+ve)[51]
 Neurosarcodiosis[52]
 Obstructive sleep apnea[53]
 Proliferative diabetic retinopathy[54]
 Schizophrenia[55, 56]
 Systemic lupus erythematous[57]

Table 1.

Conditions with elevated serum S100B levels.

In all of the conditions above, serum S100B levels are elevated. It is noted that there are some sporadic reports of decreased levels, particularly in the case of diabetes and anorexia nervosa [58, 59].

The diverse nature of the pathologies with which elevated serum S100B levels are associated, coupled with the lack of functional correlation, has made mechanistic explanations difficult to say the least. While S100B is currently known to be expressed in multiple tissues, the primary source of serum S100B is believed to be of astrocytic origin [60, 61]. Therefore, for S100B levels in serum to be elevated, astrocytic S100B must be able to reach the blood, which would not normally happen due to the presence of the blood-brain barrier (BBB).

The BBB comprises the physiological and functional barrier that separates the nervous system from the circulatory system [62, 63] and its breakdown allows for the leakage of damaging humoral elements into the brain parenchyma [63, 64, 65, 66, 67].

Advertisement

4. S100B and blood-brain barrier (BBB)

4.1 BBB and neurodegenerative diseases

The BBB is mainly formed by a monolayer of brain vascular endothelial cells (BVECs) that are sealed by tight junctions (TJs) [reviewed in [68, 69, 70]]. It actively regulates transportation of metabolic wastes and nutrients, such as ions, glucose, and amino acids, between blood and brain interstitial fluid (ISF) [reviewed in [69]]. On the other hand, other plasma components such as immunoglobulins and cells such as leukocytes are restricted. Thus, the BBB enables neurons and supporting cells to receive nutrients and remove wastes. In addition, they provide protection from the immune system. The concept of the neurovascular unit (NVU), to maintain the function of the BBB in health and underlie its response during disease, has been proposed [71, 72, 73, 74].

Impaired function of the BBB has been linked to a variety of pathological conditions that affect the brain [reviewed in [62, 63, 67, 75]]. These include epilepsy [reviewed in [76]], psychiatric diseases such as neuropsychiatric lupus [77], dementias such as Parkinson’s disease [78, 79, 80], Alzheimer’s disease (AD) [81, 82, 83, 84, 85, 86], other neurodegenerative diseases such as Huntington’s disease [87], amyotrophic lateral sclerosis [88, 89], multiple sclerosis [90, 91], and those caused by viral infections [92, 93, 94]. The compromise of the BBB has been tightly linked causally or as a diagnostic marker to chronic neurodegenerative diseases such as AD [95, 96, 97] and acute conditions such as delirium [98]. Yet, the causes and consequences of the BBB breach in those diseases remain elusive. Work carried out in this laboratory has established a role for S100B in maintaining an intact BBB using a mouse (S100BKO) model [66].

4.2 S100B is essential to maintain BBB

The detection of leaked serum components, such as IgG, has been widely used to assess impairment of BBB function [64]. In a study from this laboratory by Wu and coworkers [66], vascular leaks in the brain were evaluated by immunostaining brain sections from S100BKO mice to detect extravascular IgG. Previous studies have shown that intravenous injection of pertussis toxin [PT] generates leaks in the BBB [64, 99]. Therefore, wild type and S100BKO mice were injected with PT and the effect on BBB permeability was investigated.

Extravasated IgG from the blood vessels was detected as perivascular leakage clouds marking sites of BBB breach. In wild-type mice, leak clouds were detected only upon injection of PT; in the S100BKO mice, however, they were detected even without PT injection by 6 months of age and were exacerbated by PT injection. Thus, there is an endogenous BBB deficiency in S100BKO mice, which is increased by treatment with PT. The BBB breach was chronic and age-dependent, increasing with age [66]. Thus, the system mimics the chronic, age-associated compromise of BBB in humans. In addition, selective binding of neurons by IgG was also temporally and spatially associated with these leak clouds, suggesting that neuron-binding autoantibodies are present and BBB compromise allows their access to neurons in the brain; an increase in the brain-reactive autoantibodies was also associated with increased BBB breach [66].

Interestingly, despite detectable pathology, there was very little glial response as measured by increased expression of glial fibrillary acidic protein (GFAP) [66]. Is it possible that S100B is necessary to trigger the astroglial response to neuronal injury/insult? The question remains to be answered.

The potential reason for the BBB breach, however, could be identified: Based on electron microscopic analyses, disorganization of endothelial tight junctions is proposed to cause the observed BBB breach [66].

4.3 S100B is essential to maintain blood-retinal barrier (BRB)

Tight junctions are also important for the maintenance of the blood-retinal barrier (BRB). The existence of blood-retinal barrier (BRB) is well established [100, 101, 102, 103, 104], although its similarity to the BBB remains to be completely elucidated [105, 106] and its establishment, less understood [107]. If S100B was essential for the maintenance of tight junctions in vascular endothelial cells and lack of it caused BBB breach, would similar breaches be observed BRB also? The results presented below show that this is, indeed, the case.

In untreated wild-type mice (Figure 1A), staining for IgG was restricted to within blood vessels, which indicates an intact barrier. In PT-injected wild-type mice, IgG extravasated from the blood vessels. However, the perivascular leakage clouds were not obvious while the IgG-bound ganglion cells were detected (indicated by arrows in Figure 1B). The results suggest that neuron-binding autoantibodies are present and BRB compromise allows their access to neurons in the retina. Leak clouds outside the blood vessels were observed in S100BKO mice in the absence of PT (Figure 1C). Upon PT injection of S100BKO mice, the perivascular leak clouds persist (Figure 1D). Thus, an endogenous BRB deficiency in S100BKO mice was observed. The presence of retina-specific autoantibodies was confirmed independently by Western blot analyses (Figure 1E). The result shows that their appearance is age-dependent, as in the BBB.

Figure 1.

S100BKO mice demonstrate significant BRB compromise in the retina and express retina-specific autoantibodies. Overlay of IgG immunostaining (red) with DAPI (blue) is presented from the retinal sections of untreated wild-type mice (A), PT-treated WT mice (B), S100BKO mice (C), and S100BKO mice treated with PT (D). Scale bar, 20 μm. Western blots (E) of the swine retinal protein extract were probed with pooled sera from wild-type mice (WT) or from S100BKO mice at 3 (3 Mon), 6 (6 Mon), or 9 (9 Mon) months of age. A representative result is shown. Molecular size markers are indicated alongside.

Thus, the effect of S100B deprivation leads to chronic barrier disruption in both brain and retina through disruption of the endothelial tight junctions, most likely. The details of the mechanistic aspects of the action of S100B on tight junction maintenance remain to be established: both intracellular and extracellular routes are possible [14]. An intracellular mechanism is supported by observations that S100B is expressed in endothelial cells [108, 109]; furthermore, assembling and maintaining functional tight junctions is dependent upon several signaling pathways [reviewed in [110, 111, 112]], all of which are known to be influenced by S100B: calcium homeostasis [13, 14, 113], guanylate cyclase activation [114, 115], modulation of rhoGTPases such as Rac1 [116] and protein kinase C activity [108]. Extracellularly, S100B, most likely, acts through the receptor for advanced glycation end products (RAGE) expressed on endothelial cells [117] and results in the activation of the Ras-ERK1/2-NF-κB pathway [reviewed in [14]]. This pathway regulates endothelial hyperpermeability [reviewed in [111]], particularly the assembly of TJ proteins [118]. Moreover, the expression of NF-κB itself is regulated by S100B [119, 120]. Additional receptors for S100B, such as CD166/ALCAM and Toll-Like Receptors (TLR), are also known. Therefore, extracellular S100B may also be critical for endothelial function in maintaining the BBB.

Advertisement

5. Blood-brain barrier (BBB) and neurodegenerative diseases

5.1 Autoantibodies and neurodegenerative diseases

The BBB breach allows autoantibodies in the blood vessels to gain access to neurons and other cell types, causing compromise in function and, in extreme cases, cell death. The breach itself could be generated over time through age or disorders or acutely through traumatic injuries. Debris released from sick or dead cells would now be encountered by the immune system, which would mount an antibody response, generating autoantibodies. This results in a potentially devastating feedback loop: the autoantibodies cause compromise of cells, releasing debris, which, in turn, augments the response. The only way to halt this cycle will be through the loss of the targeted antigens: either through endocytosis or receptor stripping. Typically, that would also lead to dysfunctions in neurons and other cells [121, 122].

This “positive feedback loop” hypothesis is suggested by a decreased expression of MAP2, shown to be indicative of neuronal stress [123, 124], in both in vivo [66] and in vitro model systems of BBB [125] or BRB [126] breach. Previous studies have also shown a widespread presence of brain-reactive autoantibodies in human serum [127] and changing autoantibody profiles upon disease [96, 122, 128, 129, 130]. Much evidence now suggests that BBB breakdown also contributes to acute dysfunctions such as post-operative delirium and recovery from anesthesia [131, 132]. An increase in BBB permeability, like in S100BKO mice reported here, has been observed previously in humans with age [82] and with many chronic dysfunctions Table 1. Therefore, the S100BKO mouse may serve as a useful model to mimic the status of the aged BBB. It is well documented that the elderly population is highly susceptible to neurodegenerative diseases and delirium.

Increased levels of autoimmune antibodies (generally associated with increased BBB permeability) have been reported in several diseases (reviewed in [129, 130, 131, 132, 133, 134]). A positive correlation between autoantibody prevalence and age/diseased state has propelled the idea that they are potential diagnostic tools in AD and Parkinson’s disease [122, 129, 130, 131, 132, 133, 134, 135, 136].

5.2 Toward a unified mechanism

A clear understanding of the structural components and functions of the BBB may be the key to delineating pathologies of the brain. Here, we propose the idea that neurodegeneration is a multi-step process (Figure 2) involving BBB breach, infiltration of auto antibodies and other damaging plasma components into the brain parenchyma with death of the neurons as the long-term sequelae. Multiple studies indicate that the BBB is very important to the brain health, neuronal integrity, and homeostasis; when BBB breach occurs, it allows for the extravasation of blood-borne molecules (such as Aβ42 in AD), brain-reactive antibodies, and inflammatory factors into the normally immune-privileged brain parenchyma [127, 137, 138, 139]. Access of the previously excluded and potentially damaging blood-borne plasma elements to the brain interstitium results in disruption of brain homeostasis, impaired neuronal function, and eventually, neuronal loss [64, 134, 140, 141]. Furthermore, injury or disease of the central nervous system (CNS), such as AD, causes gliosis, which is characterized by the activation of astrocytes, microglia, and other cell types.

Figure 2.

Blood-brain barrier breach, autoantibodies and neurodegeneration. A unified mechanism is proposed for neurodegenerative diseases. Early changes include changes in the NVU, serum, and other insults on the BBB. Once the BBB is breached, it leads to the extravasation of serum components and access/production of brain-reactive auto antibodies. This results in a positive feedback loop, altering homeostasis and eventually resulting in the disease phenotype through neuronal injury/death.

Insults to the BBB can be brought about by several pathological conditions and result in the compromise of this protective layer. Studies from our lab show that the inner blood-retinal barrier (BRB) is very similar to the BBB and can be used as a model system to study BBB [126]. The use of brain-reactive autoantibodies to diagnose neurodegenerative diseases with a high degree of confidence has also been reported [122, 135, 136, 142, 143, 144, 145].

Taken together, investigations into the BBB maintenance will yield rich dividends toward the mechanistic understanding that may underlie multiple neurodegenerative diseases, increased diagnostic tools in terms of model systems and biomarkers and, perhaps, also drug delivery options. Delineation of S100B signaling pathways is likely to contribute significantly toward this end.

Advertisement

6. Conclusions

S100B, primarily astrocytic in origin, is a unique signaling molecule that impacts multiple signaling pathways—sometimes negatively, sometimes positively [15, 146]. The dual nature of action—intra- and extracellular—poses a significant challenge in delineating the precise mechanism of action in many instances. Yet, S100B is emerging as a central molecule (Figure 3) in regulating normal and disease processes—especially where astrocytes/glial cells are involved—the enteric glial cells being a recent and exciting example [147]. It is hoped that a fundamental mechanistic understanding would enable decipher the process, refine the clinical relevance biomarker, and carry the laboratory bench knowledge to the patient bedside to improve quality of life and clinical interventions.

Figure 3.

A central role for S100B, an astrocytic protein. The figure depicts the multiple cell-types contributing to an intact BBB that form the NVU. By virtue of being an extracellular signal as well as being expressed intracellularly, S100B is proposed to play a central role in maintaining BBB and serve as a marker for neurodegeneration.

Advertisement

Acknowledgments

The authors are extremely grateful to excellent discussions with Professor Robert Nagele. The support for research through grants from Osteopathic Heritage Foundation and American Osteopathic Association is gratefully acknowledged.

References

  1. 1. Virchow R. Über das granulierte Ansehen der Wandlungen der Hirnventrikel. Allgemeine Zeitschrift für Psychiatrie und Psychisch-Gerichtliche Medizin. 1846;3:242
  2. 2. Kettenmann H, Verkhratsky A. Neuroglia: The 150 years after. Trends in Neurosciences. 2008;31(12):653-659
  3. 3. Cajal SR. Histology of the nervous system of man and vertebrates. In: History of Neuroscience. New York: Oxford University Press; 1995 (6)
  4. 4. Allen NJ. Astrocyte regulation of synaptic behavior. Annual Review of Cell and Developmental Biology. 2014;30:439-463
  5. 5. Butt A, Verkhratsky A. Neuroglia: Realising their true potential. Brain and Neuroscience Advances. 2018;2:1-6. DOI: 10.1177/2398212818817495
  6. 6. Greenhalgh AD, David S, Bennett FC. Immune cell regulation of glia during CNS injury and disease. Nature Reviews. Neuroscience. 2020;21(3):139-152
  7. 7. McConnell HL, Kersch CN, Woltjer RL, Neuwelt EA. The translational significance of the neurovascular unit. The Journal of Biological Chemistry. 2017;292(3):762-770
  8. 8. Michinaga S, Koyama Y. Dual roles of astrocyte-derived factors in regulation of blood-brain barrier function after brain damage. International Journal of Molecular Sciences. 2019;20(3):571-593
  9. 9. Ponath G, Park C, Pitt D. The role of astrocytes in multiple sclerosis. Frontiers in Immunology. 2018;9:217
  10. 10. Spampinato SF, Bortolotto V, Canonico PL, Sortino MA, Grilli M. Astrocyte-derived paracrine signals: Relevance for neurogenic niche regulation and blood-brain barrier integrity. Frontiers in Pharmacology. 2019;10:1346
  11. 11. Takahashi S. Metabolic compartmentalization between astroglia and neurons in physiological and pathophysiological conditions of the neurovascular unit. Neuropathology. 2020;40:121-137
  12. 12. Vainchtein ID, Molofsky AV. Astrocytes and microglia: In sickness and in health. Trends in Neurosciences. 2020;43(3):144-154
  13. 13. Donato R, Cannon BR, Sorci G, Riuzzi F, Hsu K, Weber DJ, et al. Functions of S100 proteins. Current Molecular Medicine. 2013;13(1):24-57
  14. 14. Donato R, Sorci G, Riuzzi F, Arcuri C, Bianchi R, Brozzi F, et al. S100B’s double life: Intracellular regulator and extracellular signal. Biochimica et Biophysica Acta. 2009;1793(6):1008-1022
  15. 15. Van Eldik LJ, Wainwright MS. The Janus face of glial-derived S100B: Beneficial and detrimental functions in the brain. Restorative Neurology and Neuroscience. 2003;21(3-4):97-108
  16. 16. Moore BW. A soluble protein characteristic of the nervous system. Biochemical and Biophysical Research Communications. 1965;19(6):739-744
  17. 17. Gonzalez LL, Garrie K, Turner MD. Role of S100 proteins in health and disease. Biochimica et Biophysica Acta (BBA): Molecular Cell Research. 1867;2020(6):118677
  18. 18. Matsumura H, Shiba T, Inoue T, Harada S, Kai Y. A novel mode of target recognition suggested by the 2.0 A structure of holo S100B from bovine brain. Structure. 1998;6(2):233-241
  19. 19. Wright NT, Inman KG, Levine JA, Cannon BR, Varney KM, Weber DJ. Refinement of the solution structure and dynamic properties of Ca2+-bound rat S100B. Journal of Biomolecular NMR. 2008;42(4):279-286
  20. 20. Viviano J, Krishnan A, Wu H, Venkataraman V. Electrophoretic mobility shift in native gels indicates calcium-dependent structural changes of neuronal calcium sensor proteins. Analytical Biochemistry. 2016;494:93-100
  21. 21. Bersani I, Pluchinotta F, Dotta A, Savarese I, Campi F, Auriti C, et al. Early predictors of perinatal brain damage: The role of neurobiomarkers. Clinical Chemistry and Laboratory Medicine. 2020;58(4):471-486
  22. 22. Jones CMC, Harmon C, McCann M, Gunyan H, Bazarian JJ. S100B outperforms clinical decision rules for the identification of intracranial injury on head CT scan after mild traumatic brain injury. Brain Injury. 2020:1-8
  23. 23. Dadas A, Washington J, Diaz-Arrastia R, Janigro D. Biomarkers in traumatic brain injury (TBI): A review. Neuropsychiatric Disease and Treatment. 2018;14:2989-3000
  24. 24. Kawata K, Liu CY, Merkel SF, Ramirez SH, Tierney RT, Langford D. Blood biomarkers for brain injury: What are we measuring? Neuroscience & Biobehavioral Reviews. 2016;68:460-473
  25. 25. Abbasi M, Sajjadi M, Fathi M, Maghsoudi M. Serum S100B protein as an outcome prediction tool in emergency department patients with traumatic brain injury. Turkish Journal of Emergency Medicine. 2014;14(4):147-152
  26. 26. Wang KK, Yang Z, Zhu T, Shi Y, Rubenstein R, Tyndall JA, et al. An update on diagnostic and prognostic biomarkers for traumatic brain injury. Expert Review of Molecular Diagnostics. 2018;18(2):165-180
  27. 27. Kovesdi E, Luckl J, Bukovics P, Farkas O, Pal J, Czeiter E, et al. Update on protein biomarkers in traumatic brain injury with emphasis on clinical use in adults and pediatrics. Acta Neurochirurgica. 2010;152(1):1-17
  28. 28. Manzano S, Holzinger IB, Kellenberger CJ, Lacroix L, Klima-Lange D, Hersberger M, et al. Diagnostic performance of S100B protein serum measurement in detecting intracranial injury in children with mild head trauma. Emergency Medicine Journal. 2016;33(1):42-46
  29. 29. Zonner SW, Ejima K, Bevilacqua ZW, Huibregtse ME, Charleston C, Fulgar C, et al. Association of increased serum S100B levels with high school football subconcussive head impacts. Frontiers in Neurology. 2019;10:327
  30. 30. Aydin I, Algin A, Poyraz MK, Yumrutas O. Diagnostic value of serum glial fibrillary acidic protein and S100B serum levels in emergency medicine patients with traumatic versus nontraumatic intracerebral hemorrhage. Nigerian Journal of Clinical Practice. 2018;21(12):1645-1650
  31. 31. Ferrete-Araujo AM, Rodriguez-Rodriguez A, Egea-Guerrero JJ, Vilches-Arenas A, Godoy DA, Murillo-Cabezas F. Brain injury biomarker behavior in spontaneous intracerebral hemorrhage. World Neurosurgery. 2019;132:e496-e505
  32. 32. Montaner J, Mendioroz M, Delgado P, García-Berrocoso T, Giralt D, Merino C, et al. Differentiating ischemic from hemorrhagic stroke using plasma biomarkers: The S100B/RAGE pathway. Journal of Proteomics. 2012;75(15):4758-4765
  33. 33. Glushakova OY, Glushakov AV, Miller ER, Valadka AB, Hayes RL. Biomarkers for acute diagnosis and management of stroke in neurointensive care units. Brain Circulation. 2016;2(1):28-47
  34. 34. Yuan SM. Biomarkers of cerebral injury in cardiac surgery. Anadolu Kardiyoloji Dergisi. 2014;14(7):638-645
  35. 35. Li JP, Lu L, Wang LJ, Zhang FR, Shen WF. Increased serum levels of S100B are related to the severity of cardiac dysfunction, renal insufficiency and major cardiac events in patients with chronic heart failure. Clinical Biochemistry. 2011;44(12):984-988
  36. 36. Mazzini GS, Schaf DV, Vinade ER, Horowitz E, Bruch RS, Brunm LM, et al. Increased S100B serum levels in dilated cardiomyopathy patients. Journal of Cardiac Failure. 2007;13(10):850-854
  37. 37. Papa L, Silvestri S, Brophy GM, Giordano P, Falk JL, Braga CF, et al. GFAP out-performs S100beta in detecting traumatic intracranial lesions on computed tomography in trauma patients with mild traumatic brain injury and those with extracranial lesions. Journal of Neurotrauma. 2014;31(22):1815-1822
  38. 38. Tomaszewski D, Balkota M, Rybicki Z. Regional cerebral oxygen saturation decreases during primary hip arthroplasty: An analysis of perioperative regional cerebral oxygenation (rSO2), S100 calcium-binding protein B (S100B) and glial fibrillary acidic protein (GFAP) values. A pilot study. Medical Science Monitor. 2019;25:525-531
  39. 39. Choi H, Puvenna V, Brennan C, Mahmoud S, Wang XF, Phillips M, et al. S100B and S100B autoantibody as biomarkers for early detection of brain metastases in lung cancer. Translational Lung Cancer Research. 2016;5(4):413-419
  40. 40. Charmsaz S, Hughes E, Bane FT, Tibbitts P, McIlroy M, Byrne C, et al. S100beta as a serum marker in endocrine resistant breast cancer. BMC Medicine. 2017;15(1):79
  41. 41. Harpio R, Einarsson R. S100 proteins as cancer biomarkers with focus on S100B in malignant melanoma. Clinical Biochemistry. 2004;37(7):512-518
  42. 42. Martenson ED, Hansson LO, Nilsson B, von Schoultz E, Mansson Brahme E, Ringborg U, et al. Serum S-100b protein as a prognostic marker in malignant cutaneous melanoma. Journal of Clinical Oncology. 2001;19(3):824-831
  43. 43. Karonidis A, Mantzourani M, Gogas H, Tsoutsos D. Serum S100B levels correlate with stage, N status, mitotic rate and disease outcome in melanoma patients independent to LDH. Journal of BUON. 2017;22(5):1296-1302
  44. 44. Ertekin SS, Podlipnik S, Ribero S, Molina R, Rios J, Carrera C, et al. Monthly changes in serum levels of S100B protein as a predictor of metastasis development in high-risk melanoma patients. Journal of the European Academy of Dermatology and Venereology. 2020. In press. Doi: 10.1111/jdv.16212
  45. 45. Trakas E, Domnina Y, Panigrahy A, Baust T, Callahan PM, Morell VO, et al. Serum neuronal biomarkers in neonates with congenital heart disease undergoing cardiac surgery. Pediatric Neurology. 2017;72:56-61
  46. 46. Zaigham M, Lundberg F, Olofsson P. Protein S100B in umbilical cord blood as a potential biomarker of hypoxic-ischemic encephalopathy in asphyxiated newborns. Early Human Development. 2017;112:48-53
  47. 47. Liang KG, Mu RZ, Liu Y, Jiang D, Jia TT, Huang YJ. Increased serum S100B levels in patients with epilepsy: A systematic review and meta-analysis study. Frontiers in Neuroscience. 2019;13:456
  48. 48. Meguid NA, Samir H, Bjorklund G, Anwar M, Hashish A, Koura F, et al. Altered S100 calcium-binding protein B and matrix metallopeptidase 9 as biomarkers of mesial temporal lobe epilepsy with hippocampus sclerosis. Journal of Molecular Neuroscience. 2018;66(4):482-491
  49. 49. van Munster BC, Korevaar JC, Korse CM, Bonfrer JM, Zwinderman AH, de Rooij SE. Serum S100B in elderly patients with and without delirium. International Journal of Geriatric Psychiatry. 2010;25(3):234-239
  50. 50. Li Y, Yu ZX, Ji MS, Yan J, Cai Y, Liu J, et al. A pilot study of the use of dexmedetomidine for the control of delirium by reducing the serum concentrations of brain-derived neurotrophic factor, neuron-specific enolase, and S100B in polytrauma patients. Journal of Intensive Care Medicine. 2019;34(8):674-681
  51. 51. Fujii C, Tokuda T, Ishigami N, Mizuno T, Nakagawa M. Usefulness of serum S100B as a marker for the acute phase of aquaporin-4 autoimmune syndrome. Neuroscience Letters. 2011;494(1):86-88
  52. 52. Moss BP, Patel DC, Tavee JO, Culver DA. Evaluating S100B as a serum biomarker for central neurosarcoidosis. Respiratory Medicine. 2020;162:105855
  53. 53. Rezaei F, Abbasi H, Sadeghi M, Imani MM. The effect of obstructive sleep apnea syndrome on serum S100B and NSE levels: A systematic review and meta-analysis of observational studies. BMC Pulmonary Medicine. 2020;20(1):31
  54. 54. Asadova V, Gul Z, Buyukuysal RL, Yalcinbayir O. Assessment of neuron-specific enolase, S100B and malondialdehyde levels in serum and vitreous of patients with proliferative diabetic retinopathy. International Ophthalmology. 2020;40(1):227-234
  55. 55. Sen J, Belli A. S100B in neuropathologic states: The CRP of the brain? Journal of Neuroscience Research. 2007;85(7):1373-1380
  56. 56. Yelmo-Cruz S, Morera-Fumero AL, Abreu-Gonzalez P. S100B and schizophrenia. Psychiatry and Clinical Neurosciences. 2013;67(2):67-75
  57. 57. Noris-Garcia E, Arce S, Nardin P, Lanigan ME, Acuna V, Gutierrez F, et al. Peripheral levels of brain-derived neurotrophic factor and S100B in neuropsychiatric systemic lupus erythematous. Lupus. 2018;27(13):2041-2049
  58. 58. Holtkamp K, Buhren K, Ponath G, von Eiff C, Herpertz-Dahlmann B, Hebebrand J, et al. Serum levels of S100B are decreased in chronic starvation and normalize with weight gain. Journal of Neural Transmission (Vienna). 2008;115(6):937-940
  59. 59. Riuzzi F, Chiappalupi S, Arcuri C, Giambanco I, Sorci G, Donato R. S100 proteins in obesity: Liaisons dangereuses. Cellular and Molecular Life Sciences. 2020;77(1):129-147
  60. 60. Astrand R, Unden J. Clinical use of the calcium-binding S100B protein, a biomarker for head injury. Methods in Molecular Biology. 1929;2019:679-690
  61. 61. Marchi N, Rasmussen P, Kapural M, Fazio V, Kight K, Mayberg MR, et al. Peripheral markers of brain damage and blood-brain barrier dysfunction. Restorative Neurology and Neuroscience. 2003;21(3-4):109-121
  62. 62. Sharif Y, Jumah F, Coplan L, Krosser A, Sharif K, Tubbs RS. Blood brain barrier: A review of its anatomy and physiology in health and disease. Clinical Anatomy. 2018;31(6):812-823
  63. 63. Sweeney MD, Zhao Z, Montagne A, Nelson AR, Zlokovic BV. Blood-brain barrier: From physiology to disease and back. Physiological Reviews. 2019;99(1):21-78
  64. 64. Clifford PM, Zarrabi S, Siu G, Kinsler KJ, Kosciuk MC, Venkataraman V, et al. Abeta peptides can enter the brain through a defective blood-brain barrier and bind selectively to neurons. Brain Research. 2007;1142:223-236
  65. 65. Nagele RG, Acharya NK, Han M, DeMarshall C, Kosciuk MC, Nagele EP. Blood-brain barrier (Bbb) breakdown and brain-reactive autoantibodies as a trigger for Cns diseases. Gerontologist. 2012;52:453
  66. 66. Wu H, Brown EV, Acharya NK, Appelt DM, Marks A, Nagele RG, et al. Age-dependent increase of blood-brain barrier permeability and neuron-binding autoantibodies in S100B knockout mice. Brain Research. 1637;2016:154-167
  67. 67. Zhang W, Zhu L, An C, Wang R, Yang L, Yu W, et al. Brain hemorrhages: The blood brain barrier in cerebral ischemic injury—Disruption and repair. Brain Hemorrhages. 2020. In Press. Doi: 10.1016/j.hest.2019.12.004
  68. 68. Abbott NJ, Rönnbäck L, Hansson E. Astrocyte–endothelial interactions at the blood–brain barrier. Nature Reviews Neuroscience. 2006;7(1):41-53
  69. 69. Abbott NJ, Patabendige AA, Dolman DE, Yusof SR, Begley DJ. Structure and function of the blood–brain barrier. Neurobiology of Disease. 2010;37(1):13-25
  70. 70. Zlokovic BV. Neurovascular pathways to neurodegeneration in Alzheimer’s disease and other disorders. Nature Reviews Neuroscience. 2011;12(12):723-738
  71. 71. Brown WR, Thore CR. Review: Cerebral microvascular pathology in ageing and neurodegeneration. Neuropathology and Applied Neurobiology. 2011;37(1):56-74
  72. 72. Chao YX, He BP, Tay SSW. Mesenchymal stem cell transplantation attenuates blood brain barrier damage and neuroinflammation and protects dopaminergic neurons against MPTP toxicity in the substantia nigra in a model of Parkinson’s disease. Journal of Neuroimmunology. 2009;216(1):39-50
  73. 73. Hawkins BT, Davis TP. The blood-brain barrier/neurovascular unit in health and disease. Pharmacological Reviews. 2005;57(2):173-185
  74. 74. Zlokovic BV. Neurodegeneration and the neurovascular unit. Nature Medicine. 2010;16(12):1370-1371
  75. 75. Sweeney MD, Sagare AP, Zlokovic BV. Blood-brain barrier breakdown in Alzheimer disease and other neurodegenerative disorders. Nature Reviews. Neurology. 2018;14(3):133-150
  76. 76. Gorter JA, van Vliet EA, Aronica E. Status epilepticus, blood-brain barrier disruption, inflammation, and epileptogenesis. Epilepsy & Behavior. 2015;46:13-16
  77. 77. Stock AD, Wen J, Putterman C. Neuropsychiatric lupus, the blood brain barrier, and the TWEAK/Fn14 pathway. Frontiers in Immunology. 2013;4:484
  78. 78. Cabezas R, Ávila M, Gonzalez J, El-Bachá RS, Báez E, García-Segura LM, et al. Astrocytic modulation of blood brain barrier: Perspectives on Parkinson’s disease. Frontiers in Cellular Neuroscience. 2014;8:211
  79. 79. Kortekaas R, Leenders KL, van Oostrom JC, Vaalburg W, Bart J, Willemsen AT, et al. Blood-brain barrier dysfunction in parkinsonian midbrain in vivo. Annals of Neurology. 2005;57(2):176-179
  80. 80. Pisani V, Stefani A, Pierantozzi M, Natoli S, Stanzione P, Franciotta D, et al. Increased blood-cerebrospinal fluid transfer of albumin in advanced Parkinson’s disease. Journal of Neuroinflammation. 2012;9:188
  81. 81. Clifford PM, Zarrabi S, Siu G, Kinsler KJ, Kosciuk MC, Venkataraman V, et al. Aβ peptides can enter the brain through a defective blood–brain barrier and bind selectively to neurons. Brain Research. 2007;1142:223-236
  82. 82. Farrall AJ, Wardlaw JM. Blood–brain barrier: Ageing and microvascular disease—Systematic review and meta-analysis. Neurobiology of Aging. 2009;30(3):337-352
  83. 83. Sengillo JD, Winkler EA, Walker CT, Sullivan JS, Johnson M, Zlokovic BV. Deficiency in mural vascular cells coincides with blood-brain barrier disruption in Alzheimer’s disease. Brain Pathology (Zurich, Switzerland). 2013;23(3):303-310
  84. 84. de la Torre JC. Is Alzheimer’s disease a neurodegenerative or a vascular disorder? Data, dogma, and dialectics. The Lancet Neurology. 2004;3(3):184-190
  85. 85. De La Torre JC. The vascular hypothesis of Alzheimer’s disease: Bench to bedside and beyond. Neurodegenerative Diseases. 2010;7(1-3):116-121
  86. 86. de la Torre JC. Cerebral hemodynamics and vascular risk factors: Setting the stage for Alzheimer’s disease. Journal of Alzheimer’s Disease. 2012;32(3):553-567
  87. 87. Drouin-Ouellet J, Sawiak SJ, Cisbani G, Lagace M, Kuan WL, Saint-Pierre M, et al. Cerebrovascular and blood-brain barrier impairments in Huntington’s disease: Potential implications for its pathophysiology. Annals of Neurology. 2015;78:160-177
  88. 88. Garbuzova-Davis S, Hernandez-Ontiveros DG, Rodrigues MC, Haller E, Frisina-Deyo A, Mirtyl S, et al. Impaired blood–brain/spinal cord barrier in ALS patients. Brain Research. 2012;1469:114-128
  89. 89. Winkler EA, Sengillo JD, Sullivan JS, Henkel JS, Appel SH, Zlokovic BV. Blood-spinal cord barrier breakdown and pericyte reductions in amyotrophic lateral sclerosis. Acta Neuropathologica. 2013;125(1):111-120
  90. 90. Bennett J, Basivireddy J, Kollar A, Biron KE, Reickmann P, Jefferies WA, et al. Blood–brain barrier disruption and enhanced vascular permeability in the multiple sclerosis model EAE. Journal of Neuroimmunology. 2010;229(1):180-191
  91. 91. Larsson H, Stubgaard M, Frederiksen J, Jensen M, Henriksen O, Paulson O. Quantitation of blood-brain barrier defect by magnetic resonance imaging and gadolinium-DTPA in patients with multiple sclerosis and brain tumors. Magnetic Resonance in Medicine. 1990;16(1):117-131
  92. 92. Calderón-Peláez M-A, Velandia-Romero ML, Bastidas-Legarda LY, Beltrán EO, Camacho-Ortega SJ, Castellanos JE. Dengue virus infection of blood–brain barrier cells: Consequences of severe disease. Frontiers in Microbiology. 2019;10(1435):1-15
  93. 93. Leda AR, Bertrand L, Andras IE, El-Hage N, Nair M, Toborek M. Selective disruption of the blood–brain barrier by Zika virus. Frontiers in Microbiology. 2019;10(2158):1-14
  94. 94. Li F, Wang Y, Yu L, Cao S, Wang K, Yuan J, et al. Viral infection of the central nervous system and neuroinflammation precede blood-brain barrier disruption during Japanese encephalitis virus infection. Journal of Virology. 2015;89(10):5602-5614
  95. 95. Di Marco LY, Venneri A, Farkas E, Evans PC, Marzo A, Frangi AF. Vascular dysfunction in the pathogenesis of Alzheimer’s disease—A review of endothelium-mediated mechanisms and ensuing vicious circles. Neurobiology of Disease. 2015;82:593-606
  96. 96. Nagele RG, Clifford PM, Siu G, Levin EC, Acharya NK, Han M, et al. Brain-reactive autoantibodies prevalent in human sera increase intraneuronal amyloid-beta(1-42) deposition. Journal of Alzheimer’s Disease. 2011;25(4):605-622
  97. 97. Thomas J, Lewis CLT. The End of Alzheimer’s?: A Differential Diagnosis Toward a Cure. TJLPHD, LLC; 2014. pp. 471
  98. 98. Goldwaser E, Acharya N, Nagele R. Cerebrovascular and blood-brain barrier compromise: A mechanistic link between vascular disease and Alzheimer’s disease subtypes of neurocognitive disorders. Journal of Parkinson’s Disease and Alzheimer’s Disease. 2015;2(2):10
  99. 99. Munoz JJ. Biological activities of pertussigen (pertussis toxin). Pertussis Toxin. 1985:1-18
  100. 100. Cunha-Vaz J, Bernardes R, Lobo C. Blood-retinal barrier. European Journal of Ophthalmology. 2011;21(Suppl 6):S3-S9
  101. 101. Kim JH, Kim JH, Park JA, Lee SW, Kim WJ, Yu YS, et al. Blood-neural barrier: Intercellular communication at glio-vascular interface. Journal of Biochemistry and Molecular Biology. 2006;39(4):339-345
  102. 102. Kumagai AK. Glucose transport in brain and retina: Implications in the management and complications of diabetes. Diabetes/Metabolism Research and Reviews. 1999;15(4):261-273
  103. 103. Runkle EA, Antonetti DA. The blood-retinal barrier: Structure and functional significance. Methods in Molecular Biology. 2011;686:133-148
  104. 104. Takata K, Hirano H, Kasahara M. Transport of glucose across the blood-tissue barriers. International Review of Cytology. 1997;172:1-53
  105. 105. Goncalves A, Ambrosio AF, Fernandes R. Regulation of claudins in blood-tissue barriers under physiological and pathological states. Tissue Barriers. 2013;1(3):e24782
  106. 106. Patton N, Aslam TM, MacGillivray T, Deary IJ, Dhillon B, Eikelboom RH, et al. Retinal image analysis: Concepts, applications and potential. Progress in Retinal and Eye Research. 2006;25(1):99-127
  107. 107. Diaz-Coranguez M, Ramos C, Antonetti DA. The inner blood-retinal barrier: Cellular basis and development. Vision Research. 2017;139:123-137
  108. 108. Lefranc F, Decaestecker C, Brotchi J, Heizmann CW, Dewitte O, Kiss R, et al. Co-expression/co-location of S100 proteins (S100B, S100A1 and S100A2) and protein kinase C (PKC-β, −η and -ζ) in a rat model of cerebral basilar artery vasospasm. Neuropathology and Applied Neurobiology. 2005;31(6):649-660
  109. 109. Tiu SC, Chan WY, Heizmann CW, Schäfer BW, Shu SY, Yew DT. Differential expression of S100B1 and S100A61 in the human fetal and aged cerebral cortex. Developmental Brain Research. 2000;119(2):159-168
  110. 110. De Bock M, Wang N, Decrock E, Bol M, Gadicherla AK, Culot M, et al. Endothelial calcium dynamics, connexin channels and blood–brain barrier function. Progress in Neurobiology. 2013;108:1-20
  111. 111. Kumar P, Shen Q , Pivetti CD, Lee ES, Wu MH, Yuan SY. Molecular mechanisms of endothelial hyperpermeability: Implications in inflammation. Expert Reviews in Molecular Medicine. 2009;11:20-e19
  112. 112. Muldoon LL, Alvarez JI, Begley DJ, Boado RJ, Del Zoppo GJ, Doolittle ND, et al. Immunologic privilege in the central nervous system and the blood-brain barrier. Journal of Cerebral Blood Flow and Metabolism. 2013;33(1):13-21
  113. 113. Venkataraman V, Nagele RG. Calcium-sensitive ROS-GC1 signaling outside of photoreceptors: A common theme. Molecular and Cellular Biochemistry. 2002;230(1-2):117-124
  114. 114. Duda T, Koch KW, Venkataraman V, Lange C, Beyermann M, Sharma RK. Ca2+ sensor S100beta-modulated sites of membrane guanylate cyclase in the photoreceptor-bipolar synapse. The EMBO Journal. 2002;21(11):2547-2556
  115. 115. Pozdnyakov N, Goraczniak R, Margulis A, Duda T, Sharma RK, Yoshida A, et al. Structural and functional characterization of retinal calcium-dependent guanylate cyclase activator protein (CD-GCAP): Identity with S100beta protein. Biochemistry. 1997;36(46):14159-14166
  116. 116. Brozzi F, Arcuri C, Giambanco I, Donato R. S100B protein regulates astrocyte shape and migration via interaction with Src kinase: Implications for astrocyte development, activation, and tumor growth. The Journal of Biological Chemistry. 2009;284(13):8797-8811
  117. 117. Zhao Z, Sagare AP, Ma Q , Halliday MR, Kong P, Kisler K, et al. Central role for PICALM in amyloid-beta blood-brain barrier transcytosis and clearance. Nature Neuroscience. 2015;18(7):978-987
  118. 118. Aveleira CA, Lin CM, Abcouwer SF, Ambrosio AF, Antonetti DA. TNF-alpha signals through PKCzeta/NF-kappaB to alter the tight junction complex and increase retinal endothelial cell permeability. Diabetes. 2010;59(11):2872-2882
  119. 119. Hofmann MA, Drury S, Fu C, Qu W, Taguchi A, Lu Y, et al. RAGE mediates a novel proinflammatory axis: A central cell surface receptor for S100/calgranulin polypeptides. Cell. 1999;97(7):889-901
  120. 120. Valencia JV, Mone M, Zhang J, Weetall M, Buxton FP, Hughes TE. Divergent pathways of gene expression are activated by the RAGE ligands S100b and AGE-BSA. Diabetes. 2004;53(3):743-751
  121. 121. Goldwaser EL, Acharya NK, Wu H, Godsey GA, Sarkar A, DeMarshall CA, et al. Evidence that brain-reactive autoantibodies contribute to chronic neuronal internalization of exogenous amyloid-beta1-42 and key cell surface proteins during Alzheimer’s disease pathogenesis. Journal of Alzheimer’s Disease. 2020;74:345-361
  122. 122. Nagele EP, Han M, Acharya NK, DeMarshall C, Kosciuk MC, Nagele RG. Natural IgG autoantibodies are abundant and ubiquitous in human sera, and their number is influenced by age, gender, and disease. PLoS One. 2013;8(4):e60726
  123. 123. Di Stefano G, Casoli T, Fattoretti P, Gracciotti N, Solazzi M, Bertoni-Freddari C. Distribution of map2 in hippocampus and cerebellum of young and old rats by quantitative immunohistochemistry. The Journal of Histochemistry and Cytochemistry. 2001;49(8):1065-1066
  124. 124. Okamoto M, Matsumoto M, Ohtsuki T, Taguchi A, Mikoshiba K, Yanagihara T, et al. Internucleosomal DNA cleavage involved in ischemia-induced neuronal death. Biochemical and Biophysical Research Communications. 1993;196(3):1356-1362
  125. 125. Sedeyn JC, Wu H, Hobbs RD, Levin EC, Nagele RG, Venkataraman V. Histamine induces Alzheimer’s disease-like blood brain barrier breach and local cellular responses in mouse brain organotypic cultures. BioMed Research International. 2015;2015:937148
  126. 126. Wu H, Rodriguez AR, Spur BW, Venkataraman V. An acute retinal model for evaluating blood retinal barrier breach and potential drugs for treatment. Journal of Visualized Experiments. 2016;115(e54619):1-8
  127. 127. Levin EC, Acharya NK, Han M, Zavareh SB, Sedeyn JC, Venkataraman V, et al. Brain-reactive autoantibodies are nearly ubiquitous in human sera and may be linked to pathology in the context of blood-brain barrier breakdown. Brain Research. 2010;1345:221-232
  128. 128. Arias C, Arrieta I, Massieu L, Tapia R. Neuronal damage and MAP2 changes induced by the glutamate transport inhibitor dihydrokainate and by kainate in rat hippocampus in vivo. Experimental Brain Research. 1997;116(3):467-476
  129. 129. D’Andrea MR. Add Alzheimer’s disease to the list of autoimmune diseases. Medical Hypotheses. 2005;64(3):458-463
  130. 130. DeMarshall C, Sarkar A, Nagele EP, Goldwaser E, Godsey G, Acharya NK, et al. Chapter One—Utility of autoantibodies as biomarkers for diagnosis and staging of neurodegenerative diseases. In: Michael JH, editor. International Review of Neurobiology. Vol. 122. Academic Press; 2015. pp. 1-51
  131. 131. Hughes CG, Morandi A, Girard TD, Riedel B, Thompson JL, Shintani AK, et al. Association between endothelial dysfunction and acute brain dysfunction during critical illness. Anesthesiology. 2013;118(3):631-639
  132. 132. Shapiro LA, Whitaker-Azmitia PM. Expression levels of cytoskeletal proteins indicate pathological aging of S100B transgenic mice: An immunohistochemical study of MAP-2, drebrin and GAP-43. Brain Research. 2004;1019(1-2):39-46
  133. 133. Acharya NK, Nagele EP, Han M, Nagele RG. Autoantibodies: Double agents in human disease. Science Translational Medicine. 2013;5(186):186fs19
  134. 134. D’Andrea MR. Evidence linking neuronal cell death to autoimmunity in Alzheimer’s disease. Brain Research. 2003;982(1):19-30
  135. 135. Nagele E, Han M, Demarshall C, Belinka B, Nagele R. Diagnosis of Alzheimer’s disease based on disease-specific autoantibody profiles in human sera. PLoS One. 2011;6(8):e23112
  136. 136. DeMarshall CA, Nagele EP, Sarkar A, Acharya NK, Godsey G, Goldwaser EL, et al. Detection of Alzheimer’s disease at mild cognitive impairment and disease progression using autoantibodies as blood-based biomarkers. Alzheimer’s & Dementia (Amsterdam, Netherlands). 2016;3:51-62
  137. 137. Bell RD, Zlokovic BV. Neurovascular mechanisms and blood–brain barrier disorder in Alzheimer’s disease. Acta Neuropathologica. 2009;118(1):103-113
  138. 138. Grammas P. Neurovascular dysfunction, inflammation and endothelial activation: Implications for the pathogenesis of Alzheimer’s disease. Journal of Neuroinflammation. 2011;8(3):26
  139. 139. D’Andrea MR. Bursting Neurons and Fading Memories: An Alternative Hypothesis of the Pathogenesis of Alzheimer’s Disease. Academic Press; 2014
  140. 140. Bouras C, Riederer BM, Kövari E, Hof PR, Giannakopoulos P. Humoral immunity in brain aging and Alzheimer’s disease. Brain Research Reviews. 2005;48(3):477-487
  141. 141. Stein TD, Fedynyshyn JP, Kalil RE. Circulating autoantibodies recognize and bind dying neurons following injury to the brain. Journal of Neuropathology & Experimental Neurology. 2002;61(12):1100-1108
  142. 142. DeMarshall C, Goldwaser EL, Sarkar A, Godsey GA, Acharya NK, Thayasivam U, et al. Autoantibodies as diagnostic biomarkers for the detection and subtyping of multiple sclerosis. Journal of Neuroimmunology. 2017;309:51-57
  143. 143. DeMarshall C, Oh E, Kheirkhah R, Sieber F, Zetterberg H, Blennow K, et al. Detection of early-stage Alzheimer’s pathology using blood-based autoantibody biomarkers in elderly hip fracture repair patients. PLoS One. 2019;14(11):e0225178
  144. 144. Han M, Nagele E, DeMarshall C, Acharya N, Nagele R. Diagnosis of Parkinson’s disease based on disease-specific autoantibody profiles in human sera. PLoS One. 2012;7(2):e32383
  145. 145. Wen J, Stock AD, Chalmers SA, Putterman C. The role of B cells and autoantibodies in neuropsychiatric lupus. Autoimmunity Reviews. 2016;15(9):890-895
  146. 146. Donato R. Intracellular and extracellular roles of S100 proteins. Microscopy Research and Technique. 2003;60(6):540-551
  147. 147. Coelho-Aguiar JM, Verissimo CP, Costa DVS, Thomasi BBM, Frauches ACB, Ribiero FP, et al. The enteric glial network acts in the maintenance of intestinal homeostasis and in intestinal disorders. In: Astrocytes. Croatia: IntechOpen; 2019

Written By

Anuradha Krishnan, Hao Wu and Venkat Venkataraman

Submitted: March 6th, 2019 Reviewed: March 17th, 2020 Published: April 22nd, 2020