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

Alzheimer's disease (AD) is characterized by the deposition in brain of β‐amyloid (Aβ) peptides, elevated brain caspase‐3, and systemic deficiency of cytochrome c oxidase. Although increased Aβ deposition can result from mutations in amyloid precursor protein or presenilin genes, the cause of increased Aβ deposition in sporadic AD is unknown. Cytoplasmic hybrid (“cybrid”) cells made from mitochondrial DNA of nonfamilial AD subjects show antioxidant‐reversible lowering of mitochondrial membrane potential (Δ(gYm), secrete twice as much Aβ(1‐40) and Aβ(1‐42), have increased intracellular Aβ(1‐40) (1.7‐fold), and develop Congo red–positive Aβ deposits. Also elevated are cytoplasmic cytochrome c (threefold) and caspase‐3 activity (twofold). Increased AD cybrid Aβ(1‐40) secretion was normalized by inhibition of caspase‐3 or secretase and reduced by treatment with the antioxidant S(−)pramipexole. Expression of AD mitochondrial genes in cybrid cells depresses cytochrome c oxidase activity and increases oxidative stress, which, in turn, lowers ΔΨm. Under stress, cells with AD mitochondrial genes are more likely to activate cell death pathways, which drive caspase 3–mediated Aβ peptide secretion and may account for increased Aβ deposition in the AD brain. Therapeutic strategies for reducing neurodegeneration in sporadic AD can address restoration of ΔΨm and reduction of elevated Aβ secretion. Ann Neurol 2000;48:148–155