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Research article
Kelly Stauch
University of Nebraska Medical Center
Corresponding Author
ORCiD: https://orcid.org/0000-0001-7444-4403
License:
This work is licensed under a CC BY 4.0 License. Read Full License
Background
A consequence of an aging society is a continual and dramatic increase in the number of patients suffering from tauopathies, including Alzheimer’s disease (AD) and certain frontotemporal dementias. Accumulation of intracellular inclusions of abnormal fibrillar forms and hyperphosphorylated forms of microtubule-associated protein tau are hallmarks of AD and other tauopathies. Although tau pathology is associated with neuronal dysfunction the mechanism responsible remains obscure. In vitro, pathologically elevated expression of tau alters mitochondrial distribution by impairing cellular trafficking and thus may represent an important mediator of mitochondrial abnormalities contributing to neuronal dysfunction. We used the transgenic htau mouse model of tauopathy to investigate in vivo alterations in brain mitochondria in the presence of pathological forms of human tau.
Methods
In this study, we investigated alterations in bioenergetics and profiled the proteome of brain mitochondria from wild-type (WT) and htau mice at ages prior to and coinciding with pathologic tau deposition in htau mice. In addition, we characterized the expression of total and hyperphosphorylated forms of tau associated with synaptic mitochondria by biochemical fractionation and immunoblotting.
Results
Significant tau pathology-dependent alterations in synaptic mitochondrial bioenergetics were observed at 8 mo nths, but not 5 months, of agein htau mice; however, non-synaptic mitochondrial function remained unaltered. Further, compared to control mice, proteins involved in microtubule-based movement were differentially expressed in htau mice at 8 months of age. In addition, significant accumulation of tau and its hyperphosphorylated forms was observed in synaptic mitochondria isolated from 8-month-old htau mice.
Conclusion
These data suggest that tau preferentially associates with synaptic mitochondria as compared to non-synaptic mitochondria, and accumulation of pathologic forms of tau coincides with synaptic mitochondrial bioenergetic changes reminiscent of an aged synaptic mitochondrial phenotype reported in aging WT mice. Furthermore, the mitochondrially associated tau is soluble in carbonate buffer and more accessible to protease action suggesting it is not integrated into mitochochondrial membranes, but may rather be the result of protein-protein interactions.
Keywords
Aging, Bioenergetics, Proteomics, Synaptic mitochondria, Tau, Phosphorylation
Figure 1
Figure 2
Figure 3
Figure 4
Figure 5
Figure 6
This is a list of supplementary files associated with this preprint. Click to download.
- AdditionalFile1.xlsx
- FigureS1.tif
Correlation plots between triplicate samples of 8-month synaptic mitochondria. Peptide peak intensity of each WT and htau 8-month synaptic samples were compared to the biologlogical replicates within the same group by Pearson correlation. Comparison pairs are indicated within each panel.
- FigureS2.tif
Correlation plots between triplicate samples of 5-month synaptic mitochondria. Peptide peak intensity of each WT and htau 5-month synaptic samples were compared to the biologlogical replicates within the same group by Pearson correlation. Comparison pairs are indicated within each panel.
- FigureS3.tif
Correlation plots between triplicate samples of 8-month non-synaptic mitochondria. Peptide peak intensity of each WT and htau 8-month non-synaptic samples were compared to the biologlogical replicates within the same group by Pearson correlation. Comparison pairs are indicated within each panel.
- FigureS4.tif
Correlation plots between triplicate samples of 5-month non-synaptic mitochondria. Peptide peak intensity of each WT and htau 5-month non-synaptic samples were compared to the biologlogical replicates within the same group by Pearson correlation. Comparison pairs are indicated within each panel.
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This is a preprint, a preliminary version of a manuscript that has not completed peer review at a journal. Research Square does not conduct peer review prior to posting preprints. The posting of a preprint on this server should not be interpreted as an endorsement of its validity or suitability for dissemination as established information or for guiding clinical practice.
Research article
Kelly Stauch
University of Nebraska Medical Center
Corresponding Author
ORCiD: https://orcid.org/0000-0001-7444-4403
Badges
Prescreen
This manuscript passed our Prescreen assessment
Complete author information
Appropriate declaration statements
Potential risks to human health
Prescreen
History
CURRENT STATUS: Posted
Version 1
Posted 11 Feb, 2021
No community comments so far
Metrics
Comments: 0
PDF Downloads: ...
HTML Views: ...
Subject Areas
Neurology
License:
This work is licensed under a CC BY 4.0 License. Read Full License
Background
A consequence of an aging society is a continual and dramatic increase in the number of patients suffering from tauopathies, including Alzheimer’s disease (AD) and certain frontotemporal dementias. Accumulation of intracellular inclusions of abnormal fibrillar forms and hyperphosphorylated forms of microtubule-associated protein tau are hallmarks of AD and other tauopathies. Although tau pathology is associated with neuronal dysfunction the mechanism responsible remains obscure. In vitro, pathologically elevated expression of tau alters mitochondrial distribution by impairing cellular trafficking and thus may represent an important mediator of mitochondrial abnormalities contributing to neuronal dysfunction. We used the transgenic htau mouse model of tauopathy to investigate in vivo alterations in brain mitochondria in the presence of pathological forms of human tau.
Methods
In this study, we investigated alterations in bioenergetics and profiled the proteome of brain mitochondria from wild-type (WT) and htau mice at ages prior to and coinciding with pathologic tau deposition in htau mice. In addition, we characterized the expression of total and hyperphosphorylated forms of tau associated with synaptic mitochondria by biochemical fractionation and immunoblotting.
Results
Significant tau pathology-dependent alterations in synaptic mitochondrial bioenergetics were observed at 8 mo nths, but not 5 months, of agein htau mice; however, non-synaptic mitochondrial function remained unaltered. Further, compared to control mice, proteins involved in microtubule-based movement were differentially expressed in htau mice at 8 months of age. In addition, significant accumulation of tau and its hyperphosphorylated forms was observed in synaptic mitochondria isolated from 8-month-old htau mice.
Conclusion
These data suggest that tau preferentially associates with synaptic mitochondria as compared to non-synaptic mitochondria, and accumulation of pathologic forms of tau coincides with synaptic mitochondrial bioenergetic changes reminiscent of an aged synaptic mitochondrial phenotype reported in aging WT mice. Furthermore, the mitochondrially associated tau is soluble in carbonate buffer and more accessible to protease action suggesting it is not integrated into mitochochondrial membranes, but may rather be the result of protein-protein interactions.
Figure 1
Figure 2
Figure 3
Figure 4
Figure 5
Figure 6
This is a list of supplementary files associated with this preprint. Click to download.
- AdditionalFile1.xlsx
- FigureS1.tif
Correlation plots between triplicate samples of 8-month synaptic mitochondria. Peptide peak intensity of each WT and htau 8-month synaptic samples were compared to the biologlogical replicates within the same group by Pearson correlation. Comparison pairs are indicated within each panel.
- FigureS2.tif
Correlation plots between triplicate samples of 5-month synaptic mitochondria. Peptide peak intensity of each WT and htau 5-month synaptic samples were compared to the biologlogical replicates within the same group by Pearson correlation. Comparison pairs are indicated within each panel.
- FigureS3.tif
Correlation plots between triplicate samples of 8-month non-synaptic mitochondria. Peptide peak intensity of each WT and htau 8-month non-synaptic samples were compared to the biologlogical replicates within the same group by Pearson correlation. Comparison pairs are indicated within each panel.
- FigureS4.tif
Correlation plots between triplicate samples of 5-month non-synaptic mitochondria. Peptide peak intensity of each WT and htau 5-month non-synaptic samples were compared to the biologlogical replicates within the same group by Pearson correlation. Comparison pairs are indicated within each panel.
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