Alzheimer's disease cybrids replicate beta-amyloid abnormalities through cell death pathways.
Alzheimer's disease (AD) is characterized by the deposition in brain of beta-amyloid (Abeta) peptides, elevated brain caspase-3, and systemic deficiency of cytochrome c oxidase. Although increased Abeta deposition can result from mutations in amyloid precursor protein or presenilin genes, the cause of increased Abeta 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 (delta(gYm), secrete twice as much Abeta(1-40) and Abeta(1-42), have increased intracellular Abeta(1-40) (1.7-fold), and develop Congo red-positive Abeta deposits. Also elevated are cytoplasmic cytochrome c (threefold) and caspase-3 activity (twofold). Increased AD cybrid Abeta(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 delta(psi)m. Under stress, cells with AD mitochondrial genes are more likely to activate cell death pathways, which drive caspase 3-mediated Abeta peptide secretion and may account for increased Abeta deposition in the AD brain. Therapeutic strategies for reducing neurodegeneration in sporadic AD can address restoration of delta(psi)m and reduction of elevated Abeta secretion.
Khan
S M
SM
Center for the Study of Neurodegenerative Diseases, University of Virginia Health System, Charlottesville 22908, USA.
Cassarino
D S
DS
Abramova
N N
NN
Keeney
P M
PM
Borland
M K
MK
Trimmer
P A
PA
Krebs
C T
CT
Bennett
J C
JC
Parks
J K
JK
Swerdlow
R H
RH
Parker
W D
WD
Bennett
J P
JP
D000544:Alzheimer Disease / Q000378:metabolism* / Q000503:physiopathology*; D016229:Amyloid beta-Peptides / Q000378:metabolism*; D016923:Cell Death / Q000502:physiology*; D004272:DNA, Mitochondrial / Q000378:metabolism; D006801:Humans; D006822:Hybrid Cells / Q000378:metabolism*; D007150:Immunohistochemistry; D009447:Neuroblastoma; D014407:Tumor Cells, Cultured
D016229:Amyloid beta-Peptides; D004272:DNA, Mitochondrial