Abstract
Abstract 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.
Highlights
Alzheimer's disease (AD) is a neurodegenerative disorder characterized by progressive deterioration of memory and cognition
Unlike fibroblasts and peripheral blood mononuclear cells (PBMCs) from controls, which were virtually devoid of lipid droplets, cells from Alzheimer disease (AD) patients accumulated a large number of lipid droplets
The combination of low plasma HDL–C and cellular lipid accumulation is intriguing in the light of the proposed role of HDL in unloading cholesterol from tissues, including brain, and transporting it back to the liver In this respect, low high density lipoprotein cholesterol (HDL-C) levels would seem to indicate that lipid export from cells is defective in AD patients, possibly leading to increased amounts of cholesterol ester storage in the cytoplasm
Summary
Alzheimer's disease (AD) is a neurodegenerative disorder characterized by progressive deterioration of memory and cognition. A number of abnormalities in metabolic and biochemical processes described in AD brains have been found in cultured skin fibroblasts derived from AD patients, 14,15 supporting the view that AD might be seen as a systemic disorder and that fibroblasts and other peripheral cells might be useful to identify and to test hypotheses on brain pathological mechanisms leading to AD Starting from these considerations, in the present work we investigated cholesterol metabolism in skin fibroblasts and in peripheral blood mononuclear cells (PBMCs) from AD patients and their first-degree relatives as possible ex vivo models for the identification of alterations in cholesterol homeostatic regulatory pathways that may be relevant to AD development and progression. Pathways that control cholesterol esterification might represent promising targets for novel diagnostic and therapeutic AD approaches
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
