Abstract
APOE4 is the greatest genetic risk factor for late-onset Alzheimer’s disease (AD), increasing the risk of developing the disease by 3-fold in the 14% of the population that are carriers. Despite 25 years of research, the exact mechanisms underlying how APOE4 contributes to AD pathogenesis remain incompletely defined. APOE in the brain is primarily expressed by astrocytes and microglia, cell types that are now widely appreciated to play key roles in the pathogenesis of AD; thus, a picture is emerging wherein APOE4 disrupts normal glial cell biology, intersecting with changes that occur during normal aging to ultimately cause neurodegeneration and cognitive dysfunction. This review article will summarize how APOE4 alters specific pathways in astrocytes and microglia in the context of AD and the aging brain. APOE itself, as a secreted lipoprotein without enzymatic activity, may prove challenging to directly target therapeutically in the classical sense. Therefore, a deeper understanding of the underlying pathways responsible for APOE4 toxicity is needed so that more tractable pathways and drug targets can be identified to reduce APOE4-mediated disease risk.
Highlights
Alzheimer’s disease (AD) is a devastating neurodegenerative disease of aging, the incidence of which is expected to increase exponentially as the proportion of the population over the age of 65 increases
APOE Isoforms and Amyloid Clearance. Both astrocytes and microglia clear Aβ (Paresce et al, 1996; Wyss-Coray et al, 2003; Ries and Sastre, 2016) and there is some evidence that APOE4 may enhance Aβ production (Ye et al, 2005), it is widely thought that APOE4 confers AD risk through deficient Aβ clearance compared to APOE3 and APOE2 (Koistinaho et al, 2004; Deane et al, 2008; Simonovitch et al, 2016), not necessarily via direct binding (Verghese et al, 2013)
A weighted gene coexpression network analysis (WGCNA) transcriptomic analysis of brain from APOE3 or APOE4 targeted-replacement mice subjected to traumatic brain injury identified that the network most significantly associated with APOE genotype was the ‘‘innate immune response,’’ which included complement activation; in this network, the genes were shifted toward increased expression along with APOE4 compared to APOE3 (Castranio et al, 2017), again supporting a model in which APOE4 confers a pro-inflammatory phenotype relative to APOE3
Summary
Alzheimer’s disease (AD) is a devastating neurodegenerative disease of aging, the incidence of which is expected to increase exponentially as the proportion of the population over the age of 65 increases. A recent study demonstrated that blocking this microglial-dependent induction of A1 astrocytes is protective in mouse models of Parkinson’s disease (Yun et al, 2018) Whether blockade of such microglia/astrocyte cross-talk can help ameliorate neurodegeneration in humans and in AD has yet to be demonstrated. Whether APOE is one such secreted factor that mediates interactions between astrocytes and microglia has not been reported, nor has a synergistic effect of APOE from each cell type been clearly defined. Even so, since both astrocytes and microglia express APOE, this review article will separately consider specific aspects of each cell type’s normal physiology that might be impacted by APOE4 expression in aging and AD
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