Recent studies in both animal and cell models of Alzheimer’s disease (AD) indicated that sub-cellular cholesterol distribution seems to regulate amyloid-beta (Aβ) generation in the brain. In particular, cholesterol-esters (CE), rather than total cholesterol levels, appear directly correlated with Aβ production. Here we observed that, similarly to brain cells, skin fibroblasts obtained from AD patients produce and accumulate more CE than skin fibroblasts from age-matched healthy controls do. AD fibroblasts also exhibited a 2 fold increase in the expression of ACAT1, in addition to lower levels of SREBP2, nCEH, Caveolin-1 and ABCA1 mRNA levels, all of which are involved in the CE cycle. HMGCoA-reductase and LDL-receptor mRNAs levels did not show statistically significant changes in AD, compared to non-AD, cells. Furthermore, although APP mRNA did not significantly vary, neprilysin (NEP), the most important enzyme in the proteolysis of Aβ, was expressed at very low levels in skin fibroblasts of sporadic AD patients. Our results contribute to the concept that AD may be the consequence of a basic and systemic defect in the CE cycle. Moreover, our results identify new possible targets for the diagnosis, prevention, and cure or, at least, amelioration of the symptoms of AD.
Altered cholesterol ester cycle in ex vivo skin fibroblasts from Alzheimer patients
PANI, ALESSANDRA;DIAZ, GIACOMO;MULAS, CLAUDIA;ORRU', CHRISTINA DORIANA;COCCO, PIER LUIGI;
2008-01-01
Abstract
Recent studies in both animal and cell models of Alzheimer’s disease (AD) indicated that sub-cellular cholesterol distribution seems to regulate amyloid-beta (Aβ) generation in the brain. In particular, cholesterol-esters (CE), rather than total cholesterol levels, appear directly correlated with Aβ production. Here we observed that, similarly to brain cells, skin fibroblasts obtained from AD patients produce and accumulate more CE than skin fibroblasts from age-matched healthy controls do. AD fibroblasts also exhibited a 2 fold increase in the expression of ACAT1, in addition to lower levels of SREBP2, nCEH, Caveolin-1 and ABCA1 mRNA levels, all of which are involved in the CE cycle. HMGCoA-reductase and LDL-receptor mRNAs levels did not show statistically significant changes in AD, compared to non-AD, cells. Furthermore, although APP mRNA did not significantly vary, neprilysin (NEP), the most important enzyme in the proteolysis of Aβ, was expressed at very low levels in skin fibroblasts of sporadic AD patients. Our results contribute to the concept that AD may be the consequence of a basic and systemic defect in the CE cycle. Moreover, our results identify new possible targets for the diagnosis, prevention, and cure or, at least, amelioration of the symptoms of AD.
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