http://precedings.nature.com/tags/Alzheimer Recently posted documents tagged with 'Alzheimer' Nature Publishing Group en Nature Precedings http://precedings.nature.com/images/header_logo.gif http://precedings.nature.com http://precedings.nature.com/documents/1602/version/1 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. http://precedings.nature.com/documents/1602/version/1 Tue, 19 Feb 2008 12:08:52 UTC Altered cholesterol ester cycle in ex vivo skin fibroblasts from Alzheimer patients hdl:10101/npre.2008.1602.1 2008-02-19 Alessandra Pani Nature Precedings 2008-02-19T12:08:52Z Manuscript Molecular Cell Biology Neuroscience http://creativecommons.org/licenses/by/3.0/ http://precedings.nature.com/documents/1246/version/1 Background. Previous epidemiological and experimental studies indicated cholesterol as a central player in Alzheimer disease (AD). Here, we utilized skin fibroblasts and PBMC as possible ex vivo models for the study of dysfunctions of cholesterol homeostasis which may be related to AD development. Methods. We analyzed cholesterol homeostasis using colorimetric, thin layer chromatography (TLC), and histologic technique in ex vivo cultures of skin fibroblasts and PBMCs from patients with probable AD and their first-degree relatives. Additionally, healthy age-matched individuals served as controls. Findings. As compared to controls, skin fibroblasts and PBMCs from AD patients, displayed an evident alteration of cholesterol metabolism; namely an anomalous accumulation of cholesterol esters in their cytoplasm. No change in intracellular free cholesterol was observed. Cellular overloading of cholesterol esters was dramatically increased after specific growth stimulation of the different cell types. Cholesterol ester accumulation was negatively correlated to plasma levels of high density lipoprotein cholesterol (HDL-C) and positively correlated with severity of cognitive symptoms measured by Mini-Mental State Examination (MMSE). Inhibitors of cholesterol esterification, such as progesterone and SaH, as well as a potent inhibitor of cell proliferation, RAD, were able to prevent accumulation of cholesterol esters. Interpretation. Changes of cholesterol esters in the peripheral compartment may be indicative of a systemic alteration of intracellular cholesterol homeostasis, which in turn might create a cellular milieu favourable to the production of ß-amyloid in the brain. Pathways that control cholesterol esterification might represent promising targets for novel diagnostic and therapeutic AD approaches. http://precedings.nature.com/documents/1246/version/1 Thu, 08 Nov 2007 10:41:33 UTC Changes in Cholesterol Metabolism in Peripheral Cells of Alzheimer Disease Patients and Their Relatives hdl:10101/npre.2007.1246.1 2007-11-08 Alessandra Pani Nature Precedings 2007-11-08T10:41:33Z Manuscript Molecular Cell Biology Neuroscience http://creativecommons.org/licenses/by/2.5/