Apolipoprotein E isoforms and regulation of the innate immune response in brain of patients with Alzheimer's disease

Abstract

The largest genetic risk for late-onset Alzheimer's disease (AD) resides at the apolipoprotein E gene (APOE) locus, which has three common alleles (ɛ2, ɛ3, ɛ4) that encode three isoforms (apoE2, apoE3, apoE4). The very strong association of the APOE ɛ4 allele with AD risk and its role in the accumulation of amyloid β in brains of people and animal models solidify the biological relevance of apoE isoforms but do not provide mechanistic insight. The innate immune response is consistently observed in AD and is a likely contributor to neuronal injury and response to injury. Here we review emerging data showing that apoE isoform regulation of multiple facets of the innate immune response in the brain may alter AD not only through amyloid β-dependent mechanisms, but also through other, amyloid β-independent mechanisms.

Figure 1. Innate and Adaptive Immunity

Innate immune system effectors include components of the complement cascade (C1q, C3(a), C5(a)) as well as professional phagocytes (macrophages, tissue-specific dendritic cells). The adaptive arm of the immune system includes T cells, B cells, and the antibody-secreting plasma cells. Functions of innate immune system effectors are not burdened by genetic restriction as seen in adaptive responses.

Figure 2. Interaction between Aβ, Innate Immune Response, and APOE

Schematic of complex interaction between Aβ and the innate immune response and subsequent effect on Aβ aggregation, deposition and clearance. Other activators contribute as well, resulting both direct and indirect effects on neurons. There is evidence that apoE isoforms differentially regulate these processes, and thus the extent of neuron damage and Aβ burden.