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Published on: April 19, 2021
Tau Protein Mediates APP Intracellular Domain (AICD)-Induced Alzheimer's-Like Pathological Features in Mice
Kaushik Ghosal1, Qingyuan Fan1, Hana N Dawson2
1Department of Neurosciences, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio, 44195, United States of America.
Abstract:
Amyloid precursor protein (APP) is cleaved by gamma-secretase to simultaneously generate amyloid beta (Aβ) and APP Intracellular Domain (AICD) peptides. Aβ plays a pivotal role in Alzheimer's disease (AD) pathogenesis but recent studies suggest that amyloid-independent mechanisms also contribute to the disease. We previously showed that AICD transgenic mice (AICD-Tg) exhibit AD-like features such as tau pathology, aberrant neuronal activity, memory deficits and neurodegeneration in an age-dependent manner. Since AD is a tauopathy and tau has been shown to mediate Aβ-induced toxicity, we examined the role of tau in AICD-induced pathological features. We report that ablating endogenous tau protects AICD-Tg mice from deficits in adult neurogenesis, seizure severity, short-term memory deficits and neurodegeneration. Deletion of tau restored abnormal phosphorylation of NMDA receptors, which is likely to underlie hyperexcitability and associated excitotoxicity in AICD-Tg mice. Conversely, overexpression of wild-type human tau aggravated receptor phosphorylation, impaired adult neurogenesis, memory deficits and neurodegeneration. Our findings show that tau is essential for mediating the deleterious effects of AICD. Since tau also mediates Aβ-induced toxic effects, our findings suggest that tau is a common downstream factor in both amyloid-dependent and-independent pathogenic mechanisms and therefore could be a more effective drug target for therapeutic intervention in AD.
Insights
Tau protein is essential for the harmful effects of APP Intracellular Domain (AICD) in Alzheimer's disease models. Removing tau protects against AICD-induced neurodegeneration and memory loss, suggesting tau as a therapeutic target.
Area of Science:
- Neuroscience
- Molecular Biology
- Pathology
Background:
- Amyloid precursor protein (APP) cleavage generates amyloid beta (Aβ) and APP Intracellular Domain (AICD).
- Aβ is implicated in Alzheimer's disease (AD) pathogenesis, but amyloid-independent mechanisms also contribute.
- Previous studies showed AICD transgenic mice (AICD-Tg) exhibit AD-like features, including tau pathology and neurodegeneration.
Purpose of the Study:
- To investigate the role of tau in mediating AICD-induced pathological features in a mouse model.
- To determine if tau is a common downstream mediator of both amyloid-dependent and -independent AD pathologies.
Main Methods:
- Generated AICD transgenic mice (AICD-Tg) and AICD-Tg mice with tau ablated (tau knockout).
- Assessed neurogenesis, seizure severity, short-term memory, and neurodegeneration in these mouse models.
- Examined the phosphorylation status of NMDA receptors in response to tau manipulation.
Main Results:
- Ablating tau protected AICD-Tg mice from neurogenesis deficits, seizures, memory impairment, and neurodegeneration.
- Tau deletion restored abnormal NMDA receptor phosphorylation, mitigating hyperexcitability and excitotoxicity.
- Overexpressing tau aggravated NMDA receptor phosphorylation and worsened AD-like pathologies in AICD-Tg mice.
Conclusions:
- Tau is essential for mediating the detrimental effects of AICD.
- Tau acts as a common downstream mediator for both amyloid-dependent and -independent pathogenic pathways in AD.
- Targeting tau may offer a therapeutic strategy for Alzheimer's disease by addressing multiple pathogenic mechanisms.
