Apolipoprotein E isoforms and regulation of the innate immune response in brain of patients with Alzheimer's disease
Highlights
► Largest genetic risk for late-onset Alzheimer's disease resides at the APOE gene. ► Innate immune response is consistently observed in AD and a possible contributor. ► apoE isoforms regulate multiple facets of innate immune response in brain. ► apoE isoforms may alter AD through both Aβ-dependent and Aβ-independent mechanisms.
Introduction
Alzheimer's disease (AD) has rare autosomal dominant forms. However, the form of AD causing a major public health problem is late-onset AD, which is not caused by dominantly inherited mutations but rather by genes conferring genetic risk in combination with other processes that are currently ill-defined. Although the etiology and pathogenesis of late-onset AD remains obscure, a key component of all forms of AD appears to be accumulation of Aβ peptides: endoproteolytic fragments of the product of the amyloid precursor protein gene, APP. The risk of the common late-onset form of AD, probably arising from modulated age of onset, has been repeatedly associated with the apolipoprotein E gene (APOE) following pioneering work that now has been replicated in genome-wide association studies (GWAS) for AD [1, 2, 3]. The strength of the association of the APOE locus with AD is orders of magnitude greater than that of other loci. Humans have three common alleles of APOE, unlike most other mammals who possess only one allele. AD risk is greatest with inheritance of ɛ4 allele, less with ɛ3 allele, and least with ɛ2 allele, and there is a gene dosage effect. The corresponding human apoE isoforms are 299-amino acid proteins that differ in amino acids at positions 112 and 158 (Table 1) [4] and possess very well-characterized isoform-specific actions in a variety of biological contexts. ApoE is an integral constituent of many lipid transport lipoproteins, playing key roles in both particle assembly and structure, as well as receptor-mediated lipoprotein uptake via the family of cell surface LDL receptors. ApoE is synthesized principally in the liver, with a discrete pool synthesized, secreted and maintained in the CNS.
Genetic associations establish biological relevance but not mechanism of action. Although the contribution to AD risk of neighboring chromosome 19 genes for translocase of outer mitochondrial membrane (TOMM) 40 and apoC-I has not been formally excluded [5, 6], the vast majority of work has focused on APOE. The model that has emerged from studies to elucidate mechanism of action is that apoE isoform-dependent effects, with apoE4 > apoE3 > apoE2, lead to increased aggregation and deposition, decreased clearance, or both, of Aβ peptides in the cerebrum [7••].
In spite of the wealth of mechanistic data for apoE isoform-specific effects in experimental models of AD and in human neuroimaging and cerebrospinal fluid (CSF) biomarker studies, our knowledge is incomplete [8, 9, 10, 11•, 12, 13•, 14, 15••, 16].
How apoE isoforms lead to altered Aβ aggregation and deposition or clearance is not entirely clear. Several groups have suggested that differential binding of apoE isoforms to Aβ influences these processes through receptor-mediated mechanisms, thereby modulating biological activity of Aβ peptides [17, 18, 19]. However, the fundamentals of apoE isoform-dependent binding to Aβ peptides in vivo are just beginning to be explored and appear to have quite different characteristics than in vitro [20].
Here we review evidence in support of an additional, or perhaps alternate, mechanism of action: that apoE isoforms differentially regulate the innate immune response to Aβ peptides and other relevant activators in AD, which in turn influences Aβ peptide aggregation, deposition, and clearance.
Section snippets
Innate immunity and AD
Innate immunity is the portion of the immune system that defends the host through non-pathogen-specific pathways. By contrast, T cells, B cells, and antibody-secreting plasma cells of the adaptive arm mobilize in response to specific antigenic determinants. This characteristic restriction of specific pathogen recognition by adaptive immune system effectors arises through complex genetic reorganization during development (Figure 1). The net effect of the innate immune response may be beneficial,
ApoE isoforms in the regulation of innate immunity
While associations between APOE and amyotrophic lateral sclerosis, multiple sclerosis, Parkinson's disease, stroke, vascular dementia, and other disorders have been proposed, the strongest evidence to date is between APOE and disease risk for AD [7••]. ApoE isoforms have been proposed to possess Aβ-dependent and Aβ-independent mechanisms by which they influence the initiation and progression of AD [59]. Immune activation is a prominent feature of AD in autopsy material, in which microglia
Conclusion
Accumulation of Aβ peptides in cerebrum appears to be a central event in the initiation or progression of AD. Aβ peptides are pleiotropic neurotoxins that can directly damage neurons; they also can activate microglia to adopt a neurotoxic phenotype, and thus indirectly damage neurons.
ApoE also is a pleiotropic molecule with multiple actions, at least some of which vary among its three common isoforms. Several laboratories have now reproducibly shown that microglial activation to a neurotoxic
References and recommended reading
Papers of particular interest, published within the period of review, have been highlighted as:
• of special interest
•• of outstanding interest
Acknowledgements
This work was supported by AG05136, AG00258, and ES16754 as well as the Nancy and Buster Alvord Endowment.
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