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Truncated tau and A? cooperatively impair mitochondria in primary neurons.

ABSTRACT: Mitochondrial dysfunction is likely a significant contributing factor to Alzheimer disease pathogenesis, and both amyloid peptide (A?) and pathological forms of tau may contribute to this impairment. Cleavage of tau at Asp421 occurs early in Alzheimer disease, and Asp421-cleaved tau likely negatively impacts neuronal function. Previously we showed that expression of Asp421-cleaved tau in a neuronal cell model resulted in mitochondrial impairment. To extend these findings we expressed either full length tau or Asp421-cleaved tau (truncated tau) in primary cortical neurons and measured different aspects of mitochondrial function with or without the addition of sublethal concentrations of A?. The expression of truncated tau alone induced significant mitochondrial fragmentation in neurons. When truncated tau expression was combined with A? at sublethal concentrations, increases in the stationary mitochondrial population and the levels of oxidative stress in cortical neurons were observed. Truncated tau expression also enhanced A?-induced mitochondrial potential loss in primary neurons. These new findings show that Asp421-cleaved tau and A? cooperate to impair mitochondria, which likely contributes to the neuronal dysfunction in Alzheimer disease.

SUBMITTER: Quintanilla RA

PROVIDER: S-EPMC3140623 | biostudies-literature | 2012 Mar

REPOSITORIES: biostudies-literature

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Truncated tau and Aβ cooperatively impair mitochondria in primary neurons.

Quintanilla Rodrigo A RA Dolan Philip J PJ Jin Youngnam N YN Johnson Gail V W GV

Neurobiology of aging 20110329 3

Mitochondrial dysfunction is likely a significant contributing factor to Alzheimer disease pathogenesis, and both amyloid peptide (Aβ) and pathological forms of tau may contribute to this impairment. Cleavage of tau at Asp421 occurs early in Alzheimer disease, and Asp421-cleaved tau likely negatively impacts neuronal function. Previously we showed that expression of Asp421-cleaved tau in a neuronal cell model resulted in mitochondrial impairment. To extend these findings we expressed either full ...[more]

PMID: 21450370

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Project description:BackgroundThe spread of tau pathology in Alzheimer's disease (AD) is mediated by cell-to-cell transmission of pathological tau seeds released from neurons that, upon internalization by recipient neurons, template the misfolding of naïve cellular tau, thereby propagating fibrillization. We hypothesize that anti-tau monoclonal antibodies (mAbs) that selectively bind to pathological tau seeds will inhibit propagation of tau aggregates and reduce the spread of tau pathology in vivo.MethodsWe inoculated mice with human AD brain-derived extracts containing tau paired helical filaments (AD-tau) and identified two novel mAbs, DMR7 and SKT82, that selectively bind to a misfolded pathological conformation of tau relative to recombinant tau monomer. To evaluate the effects of these mAbs on the spread of pathological tau in vivo, 5xFAD mice harboring significant brain Aβ plaque burden were unilaterally injected with AD-tau in the hippocampus, to initiate the formation of neuritic plaque (NP) tau pathology, and were treated weekly with intraperitoneal (i.p.) injections of DMR7, SKT82, or IgG isotype control mAbs.ResultsDMR7 and SKT82 bind epitopes comprised of the proline-rich domain and c-terminal region of tau and binding is reduced upon disruption of the pathological conformation of AD-tau by chemical and thermal denaturation. We found that both DMR7 and SKT82 immunoprecipitate pathological tau and significantly reduce the seeding of cellular tau aggregates induced by AD-tau in primary neurons by 60.5 + 13.8% and 82.2 + 8.3%, respectively, compared to IgG control. To investigate the mechanism of mAb inhibition, we generated pH-sensitive fluorophore-labeled recombinant tau fibrils seeded by AD-tau to track internalization of tau seeds and demonstrate that the conformation-selective tau mAbs inhibit the internalization of tau seeds. DMR7 and SKT82 treatment reduced hyperphosphorylated NP tau as measured with AT8 immunohistochemistry (IHC) staining, but did not achieve statistical significance in the contralateral cortex and SKT82 significantly reduced tau pathology in the ipsilateral hippocampus by 24.2%; p = 0.044.ConclusionsThese findings demonstrate that conformation-selective tau mAbs, DMR7 and SKT82, inhibit tau pathology in primary neurons by preventing the uptake of tau seeds and reduce tau pathology in vivo, providing potential novel therapeutic candidates for the treatment of AD.

Project description:Although the mechanisms by which mutant huntingtin (mHtt) results in Huntington's disease (HD) remain unclear, mHtt-induced mitochondrial defects were implicated in HD pathogenesis. The effect of mHtt could be mediated by transcriptional alterations, by direct interaction with mitochondria, or by both. In the present study, we tested a hypothesis that mHtt directly damages mitochondria. To test this hypothesis, we applied brain cytosolic fraction from YAC128 mice, containing mHtt, to brain non-synaptic and synaptic mitochondria from wild-type mice and assessed mitochondrial respiration with a Clark-type oxygen electrode, membrane potential and Ca2+ uptake capacity with tetraphenylphosphonium (TPP+ )- and Ca2+ -sensitive electrodes, respectively, and, reactive oxygen species production with Amplex Red assay. The amount of mHtt bound to mitochondria following incubation with mHtt-containing cytosolic fraction was greater than the amount of mHtt bound to brain mitochondria isolated from YAC128 mice. Despite mHtt binding to wild-type mitochondria, no abnormalities in mitochondrial functions were detected. This is consistent with our previous results demonstrating the lack of defects in brain mitochondria isolated from R6/2 and YAC128 mice. This, however, could be because of partial loss of mitochondrially bound mHtt during the isolation procedure. Consequently, we increased the amount of mitochondrially bound mHtt by incubating brain non-synaptic and synaptic mitochondria isolated from YAC128 mice with mHtt-containing cytosolic fraction. Despite the enrichment of YAC128 brain mitochondria with mHtt, mitochondrial functions (respiration, membrane potential, reactive oxygen species production, Ca2+ uptake capacity) remained unchanged. Overall, our results suggest that mHtt does not directly impair mitochondrial functions, arguing against the involvement of this mechanism in HD pathogenesis. Open Science: This manuscript was awarded with the Open Materials Badge For more information see: https://cos.io/our-services/open-science-badges/.

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Truncated tau and A? cooperatively impair mitochondria in primary neurons.

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Truncated tau and Aβ cooperatively impair mitochondria in primary neurons.

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