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

Article type: Research Article

Authors: Pani, Alessandra^a; | Dessì, Sandra^a; | Diaz, Giacomo^{a; *;} | La Colla, Paolo^a | Abete, Claudia^a | Mulas, Claudia^a | Angius, Fabrizio^a | Cannas, Maria D.^a | Orru, Christina D.^a | Cocco, Pier Luigi^{a; e} | Mandas, Antonella^b | Putzu, Paolo^c | Laurenzana, Anna^e | Cellai, Cristina^e | Costanza, Antonio Mitidieri^d | Bavazzano, Antonio^d | Mocali, Alessandra^e | Paoletti, Francesco^e;

Affiliations: [a] Department of Biomedical Sciences and Technologies, University of Cagliari, Italy | [b] Department of Internal Medical Science, University of Cagliari, Italy | [c] Alzheimer Center, ASL 8, Cagliari, Italy | [d] Azienda ASL 4, Geriatric Unit of Prato Hospital, Prato, Italy | [e] Department of Experimental Pathology and Oncology, University of Florence, Italy

Correspondence: [*] Corresponding author: Prof. Giacomo Diaz, Department of Biomedical Sciences and Technologies, University of Cagliari, Via Porcell, 4, 09100 Cagliari, Italy. Tel.: +39 070 6758430; Fax: +39 070 662574; E-mail: [email protected].

Note: [1] These authors contributed equally to this work.

Abstract: Intracellular cholesterol metabolism was reported to modulate amyloid-β (Aβ) 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-β protein precursor (AβPP) were virtually unchanged. Notably, mRNA levels of both β-site AβPP-cleaving enzyme 1 (BACE1) and neprilysin were significantly down-regulated. An increase in Aβ40; and Aβ42; 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.

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

DOI: 10.3233/JAD-2009-1193

Journal: Journal of Alzheimer's Disease, vol. 18, no. 4, pp. 829-841, 2009