title: Altered cholesterol ester cycle in skin fibroblasts from patients with Alzheimer's disease.
abstract: Intracellular cholesterol metabolism was reported to modulate amyloid-beta (Abeta) generation in Alzheimer's disease (AD). Results presented herein demonstrated that, like brain cells, cultured skin fibroblasts from AD patients contained more cholesterol esters than fibroblasts from healthy subjects. Particularly, Oil Red-O, Nile Red, and filipin staining highlighted higher levels of neutral lipids which responded to inhibitors of acyl-coenzyme A:cholesterol acyl-transferase (ACAT-1), associated with an increase in free cholesterol. ACAT-1 mRNA levels increased significantly in AD fibroblasts, whereas those of sterol regulatory element binding protein-2, neutral cholesterol ester hydrolase, and ATP-binding cassette transporter member 1 were markedly down-regulated. Instead, mRNA levels of low-density lipoprotein receptor, hydroxy-methyl-glutaryl-coenzyme A reductase, caveolin-1, and amyloid-beta protein precursor (AbetaPP) were virtually unchanged. Notably, mRNA levels of both beta-site AbetaPP-cleaving enzyme 1 (BACE1) and neprilysin were significantly down-regulated. An increase in Abeta(40) and Abeta(42) immunostaining and a decrease in BACE1 active form were also found in AD versus control fibroblasts. Altogether, these findings support the hypothesis that the derangement of cholesterol homeostasis is a systemic alteration involving central but also peripheral cells of AD patients, and point to cholesterol ester levels in AD fibroblasts as an additional metabolic hallmark useful in the laboratory and clinical practice.
authors.affiliation: Department of Biomedical Sciences and Technologies, University of Cagliari, 09100 Cagliari, Italy.
authors.forename: Alessandra
authors.initials: A
authors.lastname: Pani
authors.forename: Sandra
authors.initials: S
authors.lastname: Dessì
authors.forename: Giacomo
authors.initials: G
authors.lastname: Diaz
authors.forename: Paolo
authors.initials: P
authors.lastname: La Colla
authors.forename: Claudia
authors.initials: C
authors.lastname: Abete
authors.forename: Claudia
authors.initials: C
authors.lastname: Mulas
authors.forename: Fabrizio
authors.initials: F
authors.lastname: Angius
authors.forename: Maria D
authors.initials: MD
authors.lastname: Cannas
authors.forename: Christina D
authors.initials: CD
authors.lastname: Orru
authors.forename: Pier Luigi
authors.initials: PL
authors.lastname: Cocco
authors.forename: Antonella
authors.initials: A
authors.lastname: Mandas
authors.forename: Paolo
authors.initials: P
authors.lastname: Putzu
authors.forename: Anna
authors.initials: A
authors.lastname: Laurenzana
authors.forename: Cristina
authors.initials: C
authors.lastname: Cellai
authors.forename: Antonio Mitidieri
authors.initials: AM
authors.lastname: Costanza
authors.forename: Antonio
authors.initials: A
authors.lastname: Bavazzano
authors.forename: Alessandra
authors.initials: A
authors.lastname: Mocali
authors.forename: Francesco
authors.initials: F
authors.lastname: Paoletti
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000544:Alzheimer Disease / Q000378:metabolism*; D016229:Amyloid beta-Peptides / Q000378:metabolism; D001057:Apolipoproteins E / Q000378:metabolism; D016022:Case-Control Studies; D051242:Caveolin 1 / Q000378:metabolism; D002788:Cholesterol Esters / Q000378:metabolism*; D005260:Female; D005347:Fibroblasts / Q000378:metabolism*; D005838:Genotype; D006801:Humans; D050113:Imino Furanoses; D008297:Male; D008875:Middle Aged; D012333:RNA, Messenger / Q000235:genetics; D012867:Skin / Q000166:cytology / Q000378:metabolism
chemical_list: D016229:Amyloid beta-Peptides; D001057:Apolipoproteins E; D051242:Caveolin 1; D002788:Cholesterol Esters; D050113:Imino Furanoses; D012333:RNA, Messenger