The Role of APOE4 in Disrupting the Homeostatic Functions of Astrocytes and Microglia in Aging and Alzheimer’s Disease

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.

APOE polymorphism in ATTR amyloidosis patients treated with lipid nanoparticle siRNA

“…Variant APO E2 is associated with progress of atherosclerosis and hyperlipoproteinemia [25,26], while APO E4 carriers are prone to develop Alzheimer's disease or multiple sclerosis [27,28]. Both polymorphisms of APOE were reported to have reduced binding to hepatic receptors [14,15,29]. Thus, we speculated that TTR silencing by Patisiran shows variation between ATTR amyloidosis patients expressing different APOE genotypes.…”

Anagliptin protects neuronal cells against endogenous amyloid β (Aβ)-induced cytotoxicity and apoptosis

“…The pathological mechanisms of AD are complex. A variety of brain cells including astrocytes and microglia have been reported to participate in the pathogenesis of AD [28]. Secondly, in addition to excessive production and accumulation of Ab, a diverse range of risk factors including hyperphosphorylation of tau protein and cytokine-mediated neuroinflammation have been reported to contribute to the development of AD.…”

Regulation of Synaptic Development by Astrocyte Signaling Factors and Their Emerging Roles in Substance Abuse

“…Disruption in cholesterol metabolism in the CNS can have serious effects on membrane fluidity and neurotransmitter function, leading to severe neurological disorders such as Lemli-Opitz syndrome, Niemann-Pick (type C, C1, and C2) disease, schizophrenia, Huntington's disease, Parkinson's disease, mood disorders, as well as unipolar and bipolar depression [45]. There are three APOE polymorphic alleles in humans (e2, e3, and e4) that are the leading genetic markers for Alzheimer's disease (AD) [46,47]. The relationship between apolipoproteins and neurodegenerative disorders has been widely explored [48].…”

“…The relationship between apolipoproteins and neurodegenerative disorders has been widely explored [48]. For example, it has been established that the presence of APOE4 alters the normal function of astrocytes, as well as other glial cell types, and may therefore represent a pathogenic mechanism that contributes to neurodegenerative pathways in AD and other disorders [46].…”