Cellular cholesterol homeostasis and Alzheimer's disease

Abstract

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.

Keywords: ATP binding cassette transporter A1; acyl-coenzyme A:cholesterol acyltransferase; aging; amyloidopathy; apolipoprotein E; brain lipids; cholesterol metabolism; lipid raft; lipid trafficking; membrane contact sites; tauopathy.

Fig. 1.

Chemical structures of cholesterol and its various metabolites. This figure is reprinted from Ref. .

Fig. 2.

Cellular cholesterol trafficking. The movement of cholesterol among various subcellular compartments is governed by at least three distinct metabolic pathways, resulting in three major cholesterol pools that are not in rapid equilibration with one another. The dotted lines represent cholesterol trafficking steps not well-documented at present. See the text for details. EE, early endosome; ERC, endocytic recycling compartment.

Fig. 3.

A working model to describe the ApoE-mediated cholesterol homeostasis in astrocytes and neurons. The dotted lines represent sterol trafficking steps that are not well-documented at present. See the text for details. NR, nuclear receptor.

Fig. 4.

Beneficial effects of ACAT1_SOAT1 blockage on amyloidopathy and on tauopathy. In neurons, ACAT1_SOAT1 blockage results in reduced full-length human APP content that leads to less Aβ production; ACAT1_SOAT1 blockage also results in reduced protein content of the non-hyper-phosphorylated tau. In microglia, ACAT1_SOAT1 blockage increases Aβ clearance. See text and (224) for details.