Altered Cholesterol Ester Cycle in Skin Fibroblasts from Patients with Alzheimer's Disease

作者：Pani Alessandra; Dessi Sandra; Diaz Giacomo^*; La Colla Paolo; Abete Claudia; Mulas Claudia; Angius Fabrizio; Cannas Maria D; Orru Christina D; Cocco Pier Luigi; Mandas Antonella; Putzu Paolo; Laurenzana Anna; Cellai Cristina; Costanza Antonio Mitidieri; Bavazzano Antonio; Mocali Alessandra; Paoletti Francesco

来源：Journal of Alzheimer's Disease, 2009, 18(4): 829-841.

DOI：10.3233/JAD-2009-1193

• ACAT-1
• Alzheimer's disease (AD)
• cholesterol homeostasis
• cholesterol esterification
• filipin
• human fibroblasts
• lipids
• Nile Red
• Oil Red-O
• peripheral AD markers

Intracellular cholesterol metabolism was reported to modulate amyloid-beta (A beta) 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 (A beta PP) were virtually unchanged. Notably, mRNA levels of both beta-site A beta PP-cleaving enzyme 1 (BACE1) and neprilysin were significantly down-regulated. An increase in A beta(40) and A beta(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.

• 出版日期2009