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Truncated tau and Aβ cooperatively impair mitochondria in primary neurons
Rodrigo A Quintanilla1, Philip J Dolan, Youngnam N Jin
1Department of Anesthesiology, University of Rochester, Rochester, NY 14642, USA.
Abstract:
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 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 Aβ. The expression of truncated tau alone induced significant mitochondrial fragmentation in neurons. When truncated tau expression was combined with Aβ 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 Aβ-induced mitochondrial potential loss in primary neurons. These new findings show that Asp421-cleaved tau and Aβ cooperate to impair mitochondria, which likely contributes to the neuronal dysfunction in Alzheimer disease.
Insights
Alzheimer disease involves mitochondrial dysfunction. Asp421-cleaved tau and amyloid-beta peptide (Aβ) cooperate to impair mitochondria, worsening neuronal dysfunction in Alzheimer disease.
Area of Science:
- Neuroscience
- Cell Biology
- Biochemistry
Background:
- Mitochondrial dysfunction is a key factor in Alzheimer disease (AD) pathogenesis.
- Both amyloid-beta peptide (Aβ) and pathological tau contribute to mitochondrial impairment in AD.
- Cleavage of tau at Asp421 is an early event in AD, leading to impaired neuronal function.
Purpose of the Study:
- To investigate the combined effects of Asp421-cleaved tau and Aβ on mitochondrial function in primary cortical neurons.
- To extend previous findings on Asp421-cleaved tau-induced mitochondrial impairment.
Main Methods:
- Primary cortical neurons were transfected with either full-length tau or Asp421-cleaved tau (truncated tau).
- Mitochondrial function was assessed with and without sublethal concentrations of Aβ.
- Key parameters measured included mitochondrial fragmentation, stationary mitochondrial population, oxidative stress, and mitochondrial membrane potential.
Main Results:
- Expression of truncated tau alone caused significant mitochondrial fragmentation.
- Co-expression of truncated tau and Aβ led to increased stationary mitochondria and oxidative stress.
- Truncated tau enhanced Aβ-induced loss of mitochondrial membrane potential.
Conclusions:
- Asp421-cleaved tau and Aβ synergistically impair mitochondrial function in neurons.
- This cooperation likely contributes to the neuronal dysfunction observed in Alzheimer disease.
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