2007
DOI: 10.1002/pmic.200600728
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Proteomic and functional alterations in brain mitochondria from Tg2576 mice occur before amyloid plaque deposition

Abstract: Synaptic dysfunction is an early event in Alzheimer's disease patients and has also been detected in transgenic mouse models. In the present study, we analyzed proteomic changes in synaptosomal fractions from Tg2576 mice that overexpress mutant human amyloid precursor protein (K670N, M671L) and from their nontransgenic littermates. Cortical and hippocampal tissue was microdissected at the onset of cognitive impairment, but before deposition of amyloid plaques. Crude synaptosomal fractions were prepared by diff… Show more

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Cited by 128 publications
(83 citation statements)
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“…However, two recent studies found Aβ in the synaptosomal fractions of brain mitochondria and that Aβ diminishes the overall capacity of the ETC [63,64], suggesting that mitochondrial Aβ, localized at synapses, may be associated with synaptic damage in AD neurons. However, we do not know whether Aβ enters presynaptic mitochondria or postsynaptic mitochondria, or both, and we do not know how Aβ functionally damages synapses.…”
Section: Synaptic Aβ and Mitochondrial Dysfunctionmentioning
confidence: 99%
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“…However, two recent studies found Aβ in the synaptosomal fractions of brain mitochondria and that Aβ diminishes the overall capacity of the ETC [63,64], suggesting that mitochondrial Aβ, localized at synapses, may be associated with synaptic damage in AD neurons. However, we do not know whether Aβ enters presynaptic mitochondria or postsynaptic mitochondria, or both, and we do not know how Aβ functionally damages synapses.…”
Section: Synaptic Aβ and Mitochondrial Dysfunctionmentioning
confidence: 99%
“…Supporting the hypothesis that Aβ causes synaptic mitochondrial dysfunction in AD, Mungarro-Manchaca [63] found that the Aβ peptide potentiates mitochondrial dysfunction in the presence of ryanodine, and induces morphological changes, including mitochondrial swelling. Further, Gillardon et al [64] found Aβ oligomers in synaptosomal mitochondrial fractions and decreased energy metabolism in AD transgenic mice. The findings from these two studies suggest that in AD, the Aβ peptide may be responsible for synaptic mitochondrial damage, low ATP production, and, ultimately, the degeneration of synapses [63,64].…”
Section: Synaptic Mitochondria In Ad Neuronsmentioning
confidence: 99%
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“…1). Supporters of the amyloid cascade hypothesis have used it to explain AD-related mitochondrial pathology because: 1) AβPP and Aβ accumulates in mitochondria from brains of transgenic mice and AD subjects [144][145][146][147]; 2) binding of Aβ to the mitochondrial proteins Aβ-binding alcohol dehydrogenase and cyclophilin D is associated with increased oxidative stress, cytochrome c release, reduced mitochondrial membrane potential, and neuronal cell death [146,148]; 3) features of reduced Krebs cycle and ETC enzymatic activity, impaired state 3 and state 4 respiration, and in vivo elevation of oxidative stress demonstrated in AD and transgenic mouse brains were associated with Aβ [126,[149][150][151][152][153][154][155]; and 4) the direct reduction of cytochrome oxidase expression and activity by Aβ 42 and Aβ 25−35 (a toxic Aβ fragment) supported this hypothesis [48,156,157]. Though evidence for Aβ-induced pathology is plentiful, PET-scan measured reductions in brain glucose metabolism in MCI and AD individuals [158][159][160][161] warrant a further look at the role mitochondrial bioenergetics play.…”
Section: Mitochondrial Cascade Hypothesismentioning
confidence: 99%