Mitochondrial abnormalities in cybrid cell models of sporadic Alzheimer's disease worsen with passage in culture

Impaired platelet mitochondrial activity in Alzheimer’s disease and mild cognitive impairment

“…Also, mitochondrial involvement in AD etiology is supported by studies using a cybrid cell model, which utilizes mtDNA-depleted cultured cells re-populated with AD patient or control mitochondria. This model has been shown to recapitulate many AD features, including depressed ETC activity, increased reactive oxygen species production, reduced mitochondrial membrane potential, abnormal mitochondrial morphology, increased basal Ca 2+ level, increased cytosolic cytochrome c, increased caspase-3 activity, and increased β-amyloid secretion, increased intracellular Aβ, and the development of Congo red-positive deposits in vitro (Sheehan et al, 1997;Swerdlow et al, 1997;Cassarino et al, 1998;Khan et al, 2000;Trimmer et al, 2000Trimmer et al, , 2004Cardoso et al, 2004b). …”

Cell and animal models of mtDNA biology: progress and prospects

“…To nevertheless summarize the available data, a large number of fairly large studies using either human neuroblastoma (SH-SY5Y) or human teratocarcinoma (NT2) 0 cell backgrounds found that transfer of mtDNA from persons with Alzheimer disease generated cybrid cell lines manifesting reduced complex IV activity, increased oxidative stress, altered calcium homeostasis, mitochondrial depolarization, increased ␤-amyloid production, increased cytoplasmic cytochrome c levels, caspase 3 activation, altered intracellular stress responses, decreased mitochondrial movement, and enhanced susceptibility to exogenous ␤-amyloid exposure (10,13,17,27,29,38,54,86,88,100,115,122,125,127,128). However, a single small study of Alzheimer disease cybrids that used a HeLa 0 cell background did not reveal any deficiency of oxidative phosphorylation (49).…”

Mitochondria and Neurodegeneration

“…Studies using cybrid cells showed that the enzymatic defects can be transferred to mtDNA-deficient cells implicating mtDNA mutations. Particularly, sporadic AD platelets mitochondrial genes expressed in cybrids reduce COX activity (while the citrate synthase activity remained unchanged), reduced ATP levels and increase oxidative stress (Swerdlow et al 1997) and in long-term culture, sporadic AD cybrids develop populations of abnormal and damaged mitochondria (Trimmer et al 2004). Sporadic AD cybrids also overproduce the major amyloidogenic Ab peptides (1-40, 1-42) in a caspase-dependent manner (Khan et al 2000) and also accumulate Congo red amyloid deposits (Khan et al 2000), mimicking the amyloid plaques observed in AD brain.…”

“…Cardoso et al (2004b) have documented that the alterations in AD cybrid oxidative status renders these cells vulnerable to Ab 1-40 cell death because these cells manifest an excessive decrease in the mitochondrial membrane potential (W), excessive mitochondrial release of citochrome c and caspase enzyme activation. Continuous culture of AD cybrids, with a lowers W relative to controls, showed a worsening of the bioenergetic impairment and simultaneously an increased AD mtDNA replication, that produce mitochondria abnormalities in advance (Trimmer et al 2004). Thiffault and Bennett (2005) have studied the spontaneous W fluctuations of mitochondrial hyperpolarized with cyclosporine A.…”