Cellular cholesterol homeostasis and Alzheimer's disease

• Published in: Journal of lipid research Vol. 58; no. 12; pp. 2239 - 2254
• Main Authors: Chang, Ta-Yuan, Yamauchi, Yoshio, Hasan, Mazahir T., Chang, Catherine
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01.12.2017; Journal of Lipid Research; The American Society for Biochemistry and Molecular Biology; Elsevier
• Series: Thematic Review Series: ApoE and Lipid Homeostasis in Alzheimer’s Disease
• Subjects: acyl-coenzyme A:cholesterol acyltransferase; aging; Alleles; Alzheimer Disease - genetics; Alzheimer Disease - metabolism; Alzheimer Disease - pathology; Alzheimer's disease; Amyloid beta-Peptides - genetics; Amyloid beta-Peptides - metabolism; Amyloid beta-Protein Precursor - genetics; Amyloid beta-Protein Precursor - metabolism; Amyloid precursor protein; amyloidopathy; Animals; Apolipoprotein E; Apolipoprotein E4; Apolipoprotein E4 - genetics; Apolipoprotein E4 - metabolism; ATP binding cassette transporter A1; Bile; Biological Transport; Brain - metabolism; Brain - pathology; brain lipids; Central nervous system; Cholesterol; Cholesterol - metabolism; Dementia disorders; Gene Expression Regulation; Homeostasis; Homeostasis - genetics; Humans; Inflammation; Lipid Metabolism; lipid raft; lipid trafficking; membrane contact sites; Neurodegenerative diseases; Neurofibrillary tangles; Neurofibrillary Tangles - genetics; Neurofibrillary Tangles - metabolism; Neurofibrillary Tangles - pathology; Neurotoxicity; Peptides; Senile plaques; Signal Transduction; Tau protein; tau Proteins - genetics; tau Proteins - metabolism; tauopathy; Thematic Review Series; brain lipids; lipid trafficking; acyl-coenzyme A:cholesterol acyltransferase; tauopathy; lipid raft; membrane contact sites; amyloidopathy; cholesterol metabolism; apolipoprotein E; ATP binding cassette transporter A1; aging
• ISSN: 0022-2275; 1539-7262
• DOI: 10.1194/jlr.R075630

Alzheimer's disease (AD) is the most common form of dementia in older adults. Currently, there is no cure for AD. The hallmark of AD is the accumulation of extracellular amyloid plaques composed of amyloid-β (Aβ) peptides (especially Aβ1-42) and neurofibrillary tangles, composed of hyperphosphorylated tau and accompanied by chronic neuroinflammation. Aβ peptides are derived from the amyloid precursor protein (APP). The oligomeric form of Aβ peptides is probably the most neurotoxic species; its accumulation eventually forms the insoluble and aggregated amyloid plaques. ApoE is the major apolipoprotein of the lipoprotein(s) present in the CNS. ApoE has three alleles, of which the Apoe4 allele constitutes the major risk factor for late-onset AD. Here we describe the complex relationship between ApoE4, oligomeric Aβ peptides, and cholesterol homeostasis. The review consists of four parts: 1) key elements involved in cellular cholesterol metabolism and regulation; 2) key elements involved in intracellular cholesterol trafficking; 3) links between ApoE4, Aβ peptides, and disturbance of cholesterol homeostasis in the CNS; 4) potential lipid-based therapeutic targets to treat AD. At the end, we recommend several research topics that we believe would help in better understanding the connection between cholesterol and AD for further investigations.