title: 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 theApoe4allele 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.
authors.affiliation: Department of Biochemistry and Cell Biology, Geisel School of Medicine at Dartmouth, Hanover, NH Ta.Yuan.Chang@Dartmouth.edu Catherine.Chang@Dartmouth.edu.
authors.forename: Ta-Yuan
authors.initials: TY
authors.lastname: Chang
authors.affiliation: Nutri-Life Science Laboratory, Department of Applied Biological Chemistry, Graduate School of Agricultural and Life Sciences, University of Tokyo, Tokyo, Japan.
authors.forename: Yoshio
authors.initials: Y
authors.lastname: Yamauchi
authors.affiliation: Laboratory of Memory Circuits, Achucarro Basque Center for Neuroscience, Zamudio, Spain.
authors.forename: Mazahir T
authors.initials: MT
authors.lastname: Hasan
authors.affiliation: Department of Biochemistry and Cell Biology, Geisel School of Medicine at Dartmouth, Hanover, NH Ta.Yuan.Chang@Dartmouth.edu Catherine.Chang@Dartmouth.edu.
authors.forename: Catherine
authors.initials: C
authors.lastname: Chang
mesh_terms: D000544:Alzheimer Disease / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D016229:Amyloid beta-Peptides / Q000235:genetics / Q000378:metabolism; D016564:Amyloid beta-Protein Precursor / Q000235:genetics / Q000378:metabolism; D000818:Animals; D053327:Apolipoprotein E4 / Q000235:genetics / Q000378:metabolism*; D001692:Biological Transport; D001921:Brain / Q000378:metabolism* / Q000473:pathology; D002784:Cholesterol / Q000378:metabolism*; D005786:Gene Expression Regulation; D006706:Homeostasis / Q000235:genetics; D006801:Humans; D050356:Lipid Metabolism; D016874:Neurofibrillary Tangles / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D015398:Signal Transduction; D016875:tau Proteins / Q000235:genetics / Q000378:metabolism
chemical_list: D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; D053327:Apolipoprotein E4; C054369:MAPT protein, human; D016875:tau Proteins; D002784:Cholesterol
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