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.
Highlights
Alzheimer’s disease (AD) is the most common form of dementia in older adults
This process depends on the ABCA1, which is a multi-span membrane protein mainly enriched at the plasma membrane (PM) [reviewed in [28]]
Cholesterol is practically insoluble in water; various transport mechanisms are needed in order to catalyze the movement and the recycling of cholesterol within the cell
Summary
All mammalian cells, including cells in the CNS, possess the capacity to biosynthesize cholesterol de. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. Mevalonic acid contains five carbons and is the obligatory precursor for producing many naturally occurring organic substances, including sterols and nonsterols. Most of the mevalonic acid is converted through a series of biochemical reactions to lanosterol, which is the first sterol precursor with 30 carbons. Through several additional enzymatic reactions that occur mostly at the endoplasmic reticulum (ER) membrane, lanosterol is converted to cholesterol, a sterol with 27 carbons. A detailed review covering various aspects of the sterol biosynthetic pathway is available [3].
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