Altered cholesterol ester cycle in skin fibroblasts from patients with Alzheimer's disease.
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.
Pani
Alessandra
A
Department of Biomedical Sciences and Technologies, University of Cagliari, 09100 Cagliari, Italy.
Dessì
Sandra
S
Diaz
Giacomo
G
La Colla
Paolo
P
Abete
Claudia
C
Mulas
Claudia
C
Angius
Fabrizio
F
Cannas
Maria D
MD
Orru
Christina D
CD
Cocco
Pier Luigi
PL
Mandas
Antonella
A
Putzu
Paolo
P
Laurenzana
Anna
A
Cellai
Cristina
C
Costanza
Antonio Mitidieri
AM
Bavazzano
Antonio
A
Mocali
Alessandra
A
Paoletti
Francesco
F
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
D016229:Amyloid beta-Peptides; D001057:Apolipoproteins E; D051242:Caveolin 1; D002788:Cholesterol Esters; D050113:Imino Furanoses; D012333:RNA, Messenger