Differences of apoE isoforms in amino acid residues.
Abstract
Apolipoprotein E4 (apoE4) and outer surface protein A (ospA) are pathogenic lipoproteins involved in the progression of Alzheimer’s disease and Lyme neuroborreliosis, respectively. Results from previous studies indicate that apoE4 exhibits neurotoxicity by activating amyloid beta pathways, and ospA causes damage to the brain by stimulating immune activity of microglia and astrocytes. These results, however, lack information about the specific interactions that develop between neurons and these two lipoproteins. It is essential to investigate the effect of these lipoproteins on neuronal morphology and function to better understand the mechanism of damage and disease of the brain. This chapter summarizes previous studies on the role of apoE4 and ospA in diseases of the brain and discusses experimental results from our own work that suggests new roles for apoE4 and ospA in neuronal outgrowth and synaptic loss.
Keywords
- apolipoprotein E4
- bacterial outer surface protein A
- neurodegeneration
- neuroinflammation
- nerve regeneration
- synaptic loss
1. Introduction
Lipoproteins in the brain are involved in the onset and progression of neurodegenerative diseases (e.g., Alzheimer’s disease) [1, 2] and neuroinflammatory disorders (e.g., neuroborreliosis) [3, 4]. These lipoproteins are either endogenously expressed by astrocytes [5] and microglia [6, 7] or exogenously produced by bacterial pathogens (e.g.,
The most abundant endogenous lipoproteins in the brain include apolipoprotein E (apoE) and apoJ [2]. These endogenous lipoproteins mediate transport of lipids between various cells in the brain to maintain and regulate the brain structure and function [9, 10]. The apoE isoform, apoE4, has been investigated intensively because previous studies showed that lipidation of apoE4 (i.e., apoE4 carrying cholesterol and phospholipids) is the major risk factor indicative of the onset of Alzheimer’s disease (AD) [11].
The exogenous lipoprotein most studied in the brain is the bacterial outer surface protein A (ospA), which is produced by
Thus, apoE and ospA have been of interest to both scientists and clinicians who seek to develop new strategies for treatment of brain injuries and brain disorders induced by these pathogenic lipoproteins. It still remains unclear however, if apoE and ospA interact directly with neurons to disrupt the structure and function of the brain, whereas it is documented extensively that these lipoproteins induce pathological states via amyloid beta (Aβ) aggregation [15, 16] and immune activation of microglia and astrocytes [17, 18]. To address the absence of direct evidence of interaction between lipoproteins and neurons, we have studied the effect of apoE4 and ospA on neurons in terms of axonal outgrowth and synaptic loss. This chapter discusses these findings and the potential new roles of apoE4 and ospA in the context of previous studies on these lipoproteins in neurodegeneration and neuroinflammation.
2. ApoE4 and neuronal outgrowth
2.1. Lipidation of apoE isoforms
ApoE transports and clears lipids from one cell to another to maintain lipid homeostasis of the brain [9, 10]. To carry lipids (e.g., cholesterol, phospholipids, and lipoproteins), apoE is lipidated (i.e., lipid-bound apoE) by adenosine triphosphate (ATP)-binding cassette A1 (ABCA1) transporters on astrocytes [19] (Figure 1a). The lipidation status of apoE depends on its three isoforms (i.e., apoE2, apoE3, and apoE4) coded by three alleles (ε2, ε3, and ε4 of
ApoE isoforms | ApoE amino acid residue | |
---|---|---|
112 | 158 | |
ApoE2 | Cys | Cys |
ApoE3 | Cys | Arg |
ApoE4 | Arg | Arg |
These minor variations cause a change in the structure and function of apoE, which eventually leads to distinct disease mechanisms in AD [21]. ApoE4 has an arginine at residue 112 that connects the N terminus (Arg 61) to the C terminus (Glu 255) to form a folded structure of apoE called
When the lipidated apoE is internalized into cells, Aβ monomers and oligomers are also cleared because they bind to both lipids and apoE at residues 12–28 [23]. Thus, Aβ clearance is dependent on the structural difference of apoE isoforms, and this mechanism helps to prevent the Aβ aggregation that is associated with the progression of AD. The Aβ-bound apoE, however, forms aggregates regardless of the isoform of apoE when they are not lipidated and thus, are not internalized [16, 23] (Figure 1b).
2.2. Nonlipidated apo E4 and neuronal outgrowth
When lipidated, apoE4 is known to be toxic to neurons through various pathogenic pathways such as Aβ aggregation and apoE fragment formation [21]. The effect of apoE4 on neurons when it is not lipidated, however, remains unclear. To address this knowledge gap, the effect of apoE4 on neuronal outgrowth was studied
The mechanism by which nonlipidated apoE mediates axon outgrowth and branching remains elusive, whereas lipidated apoE is known to interact with cells via LRP1, LDLR, or HSPG [16]. It has been reported that apoE does not bind to LDLR or LRP1 without lipidation [26, 27]. Integrin and HSPGs also were tested for their involvement in apoE4-induced axon outgrowth by inhibiting these receptors. Neither of these receptors was found to be responsible for apoE4-induced neuronal outgrowth (Figure 1c). The mechanism of interaction between neurons and nonlipidated apoE4 is the subject of ongoing studies.
3. Bacterial lipoprotein and synaptic loss
3.1. Bacterial lipoproteins and neuroinflammation
Bacterial surface components including lipoproteins and lipopolysaccharide (LPS) have been reported to be elevated in the cerebrospinal fluid (CSF) of patients suffering from a bacterial infection such as bacterial meningitis [28]. These components can cause neuropsychiatric manifestations such as lymphocytic meningitis, cranial and peripheral neuropathy, and cerebral infarcts [29, 30]. When compared to LPS, bacterial lipoproteins activate inflammatory pathways more vigorously [31], leading to more severe damage to tissue [32]. Bacterial lipoproteins still remain in the tissue even after the degradation of bacteria by antibiotic therapies [33, 34]. As a result, many studies suggest that minimizing the production of bacterial proteins or inhibiting bacterial protein synthesis is more effective at preventing neural injury from bacterial infections in animal models or patients [35, 36] than simply using antibiotics to kill bacteria. Bacterial lipoproteins in the brain trigger microglia activation via the toll-like receptors (TLRs) to produce inflammatory mediators (e.g., cytokines and reactive oxygen species) [37–39] and induce migration of immune cells across the BBB [40, 41]. The result is damaged brain tissue including cell death of astrocytes, oligodendrocytes, and neurons [42, 43].
The outer surface protein (osp) is the most studied bacterial lipoprotein that includes ospA, ospB, and ospC from
3.2. OspA and presynaptic loss
OspA from
3.3. Mechanism of synaptic dysfunction induced by bacterial lipoproteins
A recent study demonstrated that viral infection leads to cognitive dysfunction by microglial engulfment of presynapses via the complement C3 pathway [53]. Another recent study showed that viral infection impairs synaptic function via glycogen synthase kinase 3 (GSK-3) activation and intracellular accumulation of Aβ [54]. Thus, an increasing number of studies are being reported that elucidate the mechanism underlying synaptic dysfunction induced by viral infection. Although there is evidence that bacterial lipoprotein ospA also damages presynapses (Figure 2), information as to how bacterial infection impairs synaptic function is lacking. Three possible mechanisms may account for synaptic dysfunction during bacterial infection. First, bacterial lipoproteins damage synapses via activation of inflammatory pathways (e.g., TLR2 and TLR4) as discussed in Section 3.1. Second, bacterial lipoproteins damage synapses through neurotransmitter-mediated excitotoxicity. It has been demonstrated that the level of quinolinic acid, the N-methyl-D-aspartate (NMDA) receptor agonist, was elevated significantly in the CSF of Lyme neuroborreliosis patients [55]. The NMDA receptor mediates synaptic transmission, plasticity, and excitotoxicity in the central nervous system (CNS) and it exhibits excitotoxic effects when an excessive flux of calcium occurs by the increase of a neurotransmitter such as glutamate [56]. However, it is yet to be determined whether the presence of bacterial lipoproteins directly mediates the elevation of quinolinic acid. Third, bacterial lipoproteins damage synapses through physical interaction with synapses independent of biochemical pathways (i.e., inflammation and receptor activation). It has been suggested that the physical properties of proteins (e.g., aggregate pattern and size) is a crucial determinant in mediating pathogenic toxicity [57, 58]. This toxicity occurs independent of their sequences or lengths [59] in a manner that is similar to the aggregation of Aβ in Alzheimer’s disease [60] or α-synuclein in Parkinson’s disease [61]. Previous studies showed that Pam3-Cys, the synthetic N-terminus of ospA, self-assembled and showed aggregating potential
4. Conclusions
This chapter describes the new roles of apoE4 and ospA as major pathogenic endogenous and exogenous lipoproteins, respectively, in neuronal outgrowth and function by discussing recent experimental data in the context of previous reports. Recent studies show that apoE4 enhances neuronal adhesion and axonal outgrowth
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