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, 42 (11), 739-746

ApoE4-Induced Cholesterol Dysregulation and Its Brain Cell Type-Specific Implications in the Pathogenesis of Alzheimer's Disease

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ApoE4-Induced Cholesterol Dysregulation and Its Brain Cell Type-Specific Implications in the Pathogenesis of Alzheimer's Disease

Woojin Jeong et al. Mol Cells.

Abstract

Significant knowledge about the pathophysiology of Alzheimer's disease (AD) has been gained in the last century; however, the understanding of its causes of onset remains limited. Late-onset AD is observed in about 95% of patients, and APOE4-encoding apolipoprotein E4 (ApoE4) is strongly associated with these cases. As an apolipoprotein, the function of ApoE in brain cholesterol transport has been extensively studied and widely appreciated. Development of new technologies such as human-induced pluripotent stem cells (hiPSCs) and CRISPR-Cas9 genome editing tools have enabled us to develop human brain model systems in vitro and readily manipulate genomic information. In the context of these advances, recent studies provide strong evidence that abnormal cholesterol metabolism by ApoE4 could be linked to AD-associated pathology. In this review, we discuss novel discoveries in brain cholesterol dysregulation by ApoE4. We further elaborate cell type-specific roles in cholesterol regulation of four major brain cell types, neurons, astrocytes, microglia, and oligodendrocytes, and how its dysregulation can be linked to AD pathology.

Keywords: Alzheimer’s disease; ApoE4; Aβ; apolipoprotein; cholesterol.

Conflict of interest statement

Disclosure

The authors have no potential conflicts of interest to disclose.

Figures

Fig. 1
Fig. 1. Cholesterol homeostasis in astrocytes
Intracellular cholesterol level is tightly regulated and maintained in astrocytes, major producers of cholesterol in the brain. When cholesterol level is low, SREBP-mediated cholesterol synthesis is triggered. If the level of cholesterol is increased, SREBP is suppressed and LXR/RXR-induced transcription for cholesterol transport proteins such as ApoE and Abca1 is facilitated. Cholesterol is also synthesized from glucose-derived Acetyl CoA, and the level of cholesterol can affect glucose metabolism.
Fig. 2
Fig. 2. Potential pathological role of cholesterol dysregulation by ApoE4 in different brain cell types
Cholesterol dysregulation by ApoE4 could lead to cell type-specific functional abnormalities in the brain such as Aβ upregulation and impaired synaptic function in neurons, reduced synapse prunning activity in astrocytes, impaired remyelination in oligodendrocytes, and Aβ accumulation and inflammatory response in microglia.

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