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.

Keywords: APOE; Alzheimer’s disease; aging; astrocytes; microglia.

Figure 1

The structure of APOE isoforms. APOE is a soluble secreted protein, with N-terminal and C-terminal domains linked by a central hinge region. The N-terminal domain contains the receptor binding domain (indicated in green), and the C-terminal domain contains the lipid binding region (indicated in orange). Each isoform differs from one another at amino acid position 112 and 158. Cysteine at position 158 (C158) in APOE2 is thought to cause deficient receptor binding, while arginine at position 112 (R112) in APOE4 changes the conformation of the entire domain such that R61 is exposed and interacts with C255 in the C-terminal domain (red dotted line). This “domain interaction” is thought to be the biophysical basis for differences in APOE4 function compared to the other isoforms; e.g., preference for VLDL over HDL. In APOE3 and APOE2, which have C112 instead of R112, the R61 is not exposed and there is no such domain interaction.

Figure 2

Impaired lipid transport capacity of astrocytic APOE4 sensitizes neurons to degeneration during aging. Astrocytes (red) expressing APOE3 supply normal levels of cholesterol and other lipids to the cells of the brain, particularly to neurons (yellow), maintaining healthy neuronal function and cognition. Astrocytes expressing APOE4 are less inefficient at lipid transport, which, compounded with aging-associated lipid dysregulation, leads to neurodegeneration (neuron with rough edges) and is expected to predispose APOE4 carriers to Alzheimer’s disease (AD).

Figure 3

The neuroprotective transfer of toxic lipids from neurons to astrocytes results in lipid droplet formation, which is abrogated in APOE4-expressing cells. Agents or stressors that induce reactive oxygen species (ROS) formation in neurons leads to increased levels of toxic peroxidated lipids. Neurons transfer these lipids to astrocytes via APOE. With APOE3 expression, this transfer results in the formation of lipid droplets (LDs; yellow dots) in astrocytes and neuroprotection. Conversely, APOE4 expression is thought to prevent the transfer of peroxidated lipids to astrocytes, resulting in no LD formation in astrocytes and subsequent neurodegeneration.

Figure 4

Different modes of glucose metabolism are preferred in the young vs. aging brain. In the young brain, aerobic glycolysis is generally favored, resulting in increased lactate production, presumably by astrocytes, which should be supportive for increased neuronal activity. With aging, there is a shift toward oxidative phosphorylation (OxPhos) instead, resulting in increased electron transport chain (ETC) activity, increased ROS production, and more peroxidated lipids. Healthy cultured cells that are resistant to Aβ toxicity happen to exhibit a preference for aerobic glycolysis, and aerobic exercise, which is known to confer neuroprotection, elevates aerobic glycolysis. In contrast, cells from familial AD patients (PSEN1ΔE9) exhibit elevated OxPhos. While young APOE4 carriers may exhibit increased glycolytic activity, particularly in brain regions associated with AD [e.g., default mode network (DMN), entorhinal cortex], aged APOE4 carriers may exhibit elevated OxPhos instead, although more evidence to demonstrate whether and how such a metabolic shift occurs is warranted.

Figure 5

The effect of APOE4 expression on microglia is cell autonomous and triggers a DAM, pro-inflammatory phenotype with impaired homeostatic functions. Microglia expressing APOE4 vs. APOE3 tend to exhibit a disease-associated microglia (DAM)-like phenotype; this includes increased pro-inflammatory cytokine production with impaired phagocytic ability, deficient clearance of debris (including amyloid plaques), and impaired migratory ability. These changes, compounded with the pro-inflammatory phenotype associated with normal aging, result in an increased risk of developing AD.

Figure 6

APOE4 disrupts homeostatic pathways in astrocytes and microglia to cause neurodegeneration and AD. APOE4 expression and the normal aging process itself impair astrocyte and microglia physiology in specific pathways, which could theoretically be targeted to treat AD. In addition to deficient clearance of Aβ, emerging evidence specifically highlights lipid dysregulation and deficient glucose metabolism in astrocytes, and a neurodegenerative pro-inflammatory response in microglia, and to some extent in astrocytes as well. All of these pathways converge with similar deficits that occur in normal aging to ultimately lead to neurodegeneration.