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.
Highlights
Alzheimer’s disease (AD) is an age-associated neurodegenerative disorder that causes severe impairment of cognitive function leading to a drastic decline in the quality of life
We analysed the subcellular localization of histone deacetylase 6 (HDAC6) in the mouse hippocampus, a brain region important for the consolidation of memories and one of the first regions to be affected in AD patients (Mesulam, 1999)
Since Histone deacetylases (HDACs) have emerged as potential therapeutic targets to treat neurodegenerative diseases, it is of utmost importance to study the role of individual HDACs in brain function
Summary
Alzheimer’s disease (AD) is an age-associated neurodegenerative disorder that causes severe impairment of cognitive function leading to a drastic decline in the quality of life. Pathological features of AD are extracellular plaques, comprised of aggregated amyloid-b (Ab) peptides, and intraneuronal tangles that consist of aggregated and hyperphosphorylated tau protein (Haass & Selkoe, 2007; Schneider & Mandelkow, 2008). These hallmarks are accompanied by loss of neurons, impairment of neuronal functions and brain atrophy (Karow et al, 2010; Nelson, 2005; Wenk, 2003). Histone acetylation is regulated by the counteracting activities of histone acetyltransferases (HATs) and histone deacetylases (HDACs) and has been identified as a key process to regulate chromatin plasticity during memory formation (Levenson & Sweatt, 2005). HDAC inhibition is considered to be a novel promising therapeutic strategy to treat AD (Abel & Zukin, 2008; Fischer et al, 2010; Sananbenesi & Fischer, 2009)
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