Increased susceptibility to amyloid toxicity in familial Alzheimer's fibroblasts.
Much experimental evidence suggests that an imbalance in cellular redox status is a major factor in the pathogenesis of Alzheimer's disease (AD). Our previous data showed a marked increase in membrane lipoperoxidation in primary fibroblasts from familial AD (FAD) patients. In the present study, we demonstrate that when oligomeric structures of Abeta 1-40 and Abeta 1-42 are added to the culture media, they accumulate quicker near the plasma membrane, and are internalized faster and mostly in APPV717I fibroblasts than in age-matched healthy cells; this results in an earlier and sharper increase in the production of reactive oxygen species (ROS). Higher ROS production leads in turn to an increase in membrane oxidative-injury and significant impairment of cellular antioxidant capacity, giving rise to apoptotic cascade activation and finally to a necrotic outcome. In contrast, healthy fibroblasts appear more resistant to amyloid oxidative-attack, possibly as a result of their plasma membrane integrity and powerful antioxidant capacity. Our data are consistent with increasing evidence that prefibrillar aggregates, compared to mature fibrils, are likely the more toxic species of the peptides. These findings provide compelling evidence that cells bearing increased membrane lipoperoxidation are more susceptible to aggregate toxicity as a result of their reduced ability to counteract amyloid oligomeric attack.
Cecchi
Cristina
C
Department of Biochemical Sciences, University of Florence, Florence, Italy. cristina.cecchi@unifi.it <cristina.cecchi@unifi.it>
Fiorillo
Claudia
C
Baglioni
Serena
S
Pensalfini
Anna
A
Bagnoli
Silvia
S
Nacmias
Benedetta
B
Sorbi
Sandro
S
Nosi
Daniele
D
Relini
Annalisa
A
Liguri
Gianfranco
G
D000328:Adult; D000544:Alzheimer Disease / Q000235:genetics / Q000473:pathology*; D016229:Amyloid beta-Peptides / Q000378:metabolism* / Q000633:toxicity*; D000704:Analysis of Variance; D017209:Apoptosis / Q000187:drug effects; D016022:Case-Control Studies; D053148:Caspase 3 / Q000378:metabolism; D002478:Cells, Cultured; D053938:DNA Fragmentation; D004797:Enzyme-Linked Immunosorbent Assay / Q000379:methods; D045604:Extracellular Fluid / Q000378:metabolism; D005192:Family Health; D005347:Fibroblasts / Q000187:drug effects* / Q000378:metabolism*; D006801:Humans; D008875:Middle Aged; D018384:Oxidative Stress / Q000187:drug effects / Q000235:genetics; D058225:Plaque, Amyloid; D017382:Reactive Oxygen Species / Q000378:metabolism; D013778:Tetrazolium Salts; D013844:Thiazoles; D013997:Time Factors
D016229:Amyloid beta-Peptides; D017382:Reactive Oxygen Species; D013778:Tetrazolium Salts; D013844:Thiazoles; D053148:Caspase 3; C022616:thiazolyl blue