Alzheimer's disease cybrids replicate beta-amyloid abnormalities through cell death pathways

Alzheimer's disease (AD) is characterized by the deposition in brain of bet a-amyloid (A beta) peptides, elevated brain caspase-3, and systemic deficie ncy of cytochrome c oxidase, Although increased A beta deposition can resul t from mutations in amyloid precursor protein or presenilin genes, the caus e of increased A beta deposition in sporadic AD is unknown, Cytoplasmic hyb rid ("cybrid") cells made from mitochondrial DNA of nonfamilial AD subjects show antioxidant-reversible lowering of mitochondrial membrane potential ( Delta(gY(m)), secrete twice as much A beta(1-40) and A beta(1-42), have inc reased intracellular A beta(1-40) (1.7-fold), and develop Congo red-positiv e A beta deposits. Also elevated are cytoplasmic cytochrome c (threefold) a nd caspase-3 activity (twofold). Increased AD cybrid A beta(1-40) secretion was normalized by inhibition of caspase-3 or secretase and reduced by trea tment with the antioxidant S(-)pramipexole. Expression of AD mitochondria g enes in cybrid cells depresses cytochrome c oxidase activity and increases oxidative stress, which, in turn, lowers Delta Psi(m). Under stress, cells with AD mitochondrial genes are more likely to activate cell death pathways , which drive caspase 3-mediated A beta peptide secretion and may account f or increased A beta deposition in the AD brain. Therapeutic strategies for reducing neurodegeneration in sporadic AD can address restoration of Delta Psi(m) and reduction of elevated A beta secretion.