Membrane cholesterol enrichment prevents Aβ-induced oxidative stress in Alzheimer's fibroblasts.
A growing body of evidence implicates low membrane cholesterol in the pathogenesis of Alzheimer's disease (AD). Here we show that Aβ42 soluble oligomers accumulate more slowly and in reduced amount at the plasma membranes of PS-1L392V and APPV717I fibroblasts from familial AD (FAD) patients enriched in cholesterol content than at the counterpart membranes. The Aβ42-induced production of reactive oxygen species (ROS) and the increase in membrane lipoperoxidation were also prevented by high membrane cholesterol, thus resulting in a higher resistance to amyloid toxicity with respect to control fibroblasts. On the other hand, the recruitment of amyloid assemblies to the plasma membrane of cholesterol-depleted fibroblasts was significantly increased, thus triggering an earlier and sharper production of ROS and a higher membrane oxidative injury. These results identify membrane cholesterol as being key to Aβ42 oligomer accumulation at the cell surfaces and to the following Aβ42-induced cell death in AD neurons.
Pensalfini
Anna
A
Department of Biochemical Sciences, University of Florence, 50134 Florence, Italy.
Zampagni
Mariagioia
M
Liguri
Gianfranco
G
Becatti
Matteo
M
Evangelisti
Elisa
E
Fiorillo
Claudia
C
Bagnoli
Silvia
S
Cellini
Elena
E
Nacmias
Benedetta
B
Sorbi
Sandro
S
Cecchi
Cristina
C
D000328:Adult; D000368:Aged; D000544:Alzheimer Disease / Q000235:genetics / Q000473:pathology; D016229:Amyloid beta-Peptides / Q000378:metabolism* / Q000494:pharmacology; D016564:Amyloid beta-Protein Precursor / Q000235:genetics; D002462:Cell Membrane / Q000187:drug effects / Q000378:metabolism*; D002478:Cells, Cultured; D002784:Cholesterol / Q000378:metabolism*; D005260:Female; D005347:Fibroblasts / Q000378:metabolism / Q000473:pathology* / Q000648:ultrastructure; D006801:Humans; D008054:Lipid Peroxides / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D009154:Mutation / Q000235:genetics; D018384:Oxidative Stress / Q000187:drug effects*; D017382:Reactive Oxygen Species / Q000378:metabolism; D013997:Time Factors
D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; D008054:Lipid Peroxides; D017382:Reactive Oxygen Species; D002784:Cholesterol