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Reducing HDAC6 ameliorates cognitive deficits in a mouse model for Alzheimer's disease.

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 ?-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-?-mediated impairment of mitochondrial trafficking. Thus, our study suggests that targeting HDAC6 could be a suitable strategy to ameliorate cognitive decline observed in AD.

SUBMITTER: Govindarajan N

PROVIDER: S-EPMC3569653 | biostudies-literature | 2013 Jan

REPOSITORIES: biostudies-literature

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Reducing HDAC6 ameliorates cognitive deficits in a mouse model for Alzheimer's disease.

Govindarajan Nambirajan N Rao Pooja P Burkhardt Susanne S Sananbenesi Farahnaz F Schlüter Oliver M OM Bradke Frank F Lu Jianrong J Fischer André A

EMBO molecular medicine 20121126 1

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 ...[more]

PMID: 23184605

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Project description:Clinical and neuropathological studies have shown that tau pathology better correlates with the severity of dementia than amyloid plaque burden, making tau an attractive target for the cure of Alzheimer's disease. We have explored whether passive immunization with the 12A12 monoclonal antibody (26-36aa of tau protein) could improve the Alzheimer's disease phenotype of two well-established mouse models, Tg2576 and 3xTg mice. 12A12 is a cleavage-specific monoclonal antibody which selectively binds the pathologically relevant neurotoxic NH226-230 fragment (i.e. NH2htau) of tau protein without cross-reacting with its full-length physiological form(s). We found out that intravenous administration of 12A12 monoclonal antibody into symptomatic (6 months old) animals: (i) reaches the hippocampus in its biologically active (antigen-binding competent) form and successfully neutralizes its target; (ii) reduces both pathological tau and amyloid precursor protein/amyloidβ metabolisms involved in early disease-associated synaptic deterioration; (iii) improves episodic-like type of learning/memory skills in hippocampal-based novel object recognition and object place recognition behavioural tasks; (iv) restores the specific up-regulation of the activity-regulated cytoskeleton-associated protein involved in consolidation of experience-dependent synaptic plasticity; (v) relieves the loss of dendritic spine connectivity in pyramidal hippocampal CA1 neurons; (vi) rescues the Alzheimer's disease-related electrophysiological deficits in hippocampal long-term potentiation at the CA3-CA1 synapses; and (vii) mitigates the neuroinflammatory response (reactive gliosis). These findings indicate that the 20-22 kDa NH2-terminal tau fragment is crucial target for Alzheimer's disease therapy and prospect immunotherapy with 12A12 monoclonal antibody as safe (normal tau-preserving), beneficial approach in contrasting the early Amyloidβ-dependent and independent neuropathological and cognitive alterations in affected subjects.

Dataset Information

Reducing HDAC6 ameliorates cognitive deficits in a mouse model for Alzheimer's disease.

Publications

Reducing HDAC6 ameliorates cognitive deficits in a mouse model for Alzheimer's disease.

Similar Datasets

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