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Published on: March 16, 2016
Reducing HDAC6 ameliorates cognitive deficits in a mouse model for Alzheimer's disease
Nambirajan Govindarajan1, Pooja Rao, Susanne Burkhardt
1Department of Psychiatry and Psychotherapy, University Medical Center, Georg-August-University Goettingen, Goettingen, Germany.
Abstract:
Histone deacetylases (HDACs) are currently being discussed as promising therapeutic targets to treat neurodegenerative diseases. However, the role of specific HDACs in cognition and neurodegeneration remains poorly understood. Here, we investigate the function of HDAC6, a class II member of the HDAC superfamily, in the adult mouse brain. We report that mice lacking HDAC6 are cognitively normal but reducing endogenous HDAC6 levels restores learning and memory and α-tubulin acetylation in a mouse model for Alzheimer's disease (AD). Our data suggest that this therapeutic effect is, at least in part, linked to the observation that loss of HDAC6 renders neurons resistant to amyloid-β-mediated impairment of mitochondrial trafficking. Thus, our study suggests that targeting HDAC6 could be a suitable strategy to ameliorate cognitive decline observed in AD.
Insights
Targeting histone deacetylase 6 (HDAC6) shows promise for Alzheimer's disease (AD). Reducing HDAC6 levels improved memory and protected neurons from amyloid-beta effects in AD mouse models.
Area of Science:
- Neuroscience
- Molecular Biology
- Pharmacology
Background:
- Histone deacetylases (HDACs) are implicated as therapeutic targets for neurodegenerative diseases.
- The specific roles of individual HDACs, like HDAC6, in cognition and neurodegeneration are not well understood.
- Alzheimer's disease (AD) is characterized by cognitive decline and neurodegeneration.
Purpose of the Study:
- To investigate the function of HDAC6 in the adult mouse brain.
- To determine if modulating HDAC6 levels impacts cognitive function and neurodegeneration in an AD mouse model.
Main Methods:
- Investigated HDAC6 function in adult mice.
- Utilized a mouse model for Alzheimer's disease (AD).
- Assessed learning and memory, α-tubulin acetylation, and mitochondrial trafficking in neurons.
Main Results:
- Mice lacking HDAC6 exhibited normal cognition.
- Reducing endogenous HDAC6 levels restored learning and memory in an AD mouse model.
- Loss of HDAC6 protected neurons against amyloid-β-induced mitochondrial trafficking impairment and increased α-tubulin acetylation.
Conclusions:
- HDAC6 plays a role in cognitive function and neurodegeneration.
- Targeting HDAC6 may be a viable therapeutic strategy to improve cognitive decline in Alzheimer's disease.
- The therapeutic effect is partly mediated by enhanced neuronal resistance to amyloid-β toxicity via improved mitochondrial trafficking.
