Reducing HDAC6 ameliorates cognitive deficits in a mouse model for Alzheimer's disease.
Bottom Line: However, the role of specific HDACs in cognition and neurodegeneration remains poorly understood.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.
Affiliation: Department of Psychiatry and Psychotherapy, University Medical Center, Georg-August-University Goettingen, Goettingen, Germany.Show MeSH
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Mentions: While the functional consequences are unknown, recent data indicate that HDAC6 levels are dysregulated in postmortem brain samples from AD patients (Ding et al, 2008). To elucidate the role of HDAC6 in AD, Hdac6−/− mice were crossed with APPPS1-21 mice (to yield APPPS1-21-Hdac6−/− mice), which is a model for severe amyloid pathology that shows memory impairment at 8 months of age (Govindarajan et al, 2011; Radde et al, 2006). Thus, we decided to analyse cognitive function in 8-month-old APPPS1-21-Hdac6−/− mice. APPPS1-21 and wild type littermates served as control groups. First, we tested exploratory behaviour in the open field paradigm. When compared to the wild type control group, the activities of APPPS1-21 or APPPS1-21-Hdac6−/− mice were not significantly altered (Fig 3A). However, the direct comparison of APPPS1-21 to APPPS1-21-Hdac6−/− mice revealed that loss of Hdac6 rescued a mild hyperactivity phenotype observed in APPPS1-21 mice (Fig 3A). When the activity in the centre versus the periphery of the open field was analysed, no difference was observed between the groups, suggesting that basal anxiety levels were not altered (Fig 3B). In concordance with this observation, all groups showed similar performance in the elevated plus-maze test, another measure of basal anxiety (Fig 3C). In line with previous studies (Govindarajan et al, 2011), associative memory was impaired in the APPPS1-21 mice when compared to a wild type control group (Fig 3D). Interestingly, the impaired freezing behaviour exhibited by the APPPS1-21 mice was completely rescued to wild type levels in the APPPS1-21-Hdac6−/− mice, which strongly suggests that loss of Hdac6 restores associative memory function in APPPS1-21 mice (Fig 3D). Hippocampus-dependent memory function was also analysed in the Morris Water Maze test. All groups showed similar escape latencies during the 8 days of training (Fig 3E). When spatial memory function was assessed in the subsequent probe test, preference for the target quadrant was significantly impaired in APPPS1-21 mice when compared to wild type control group (Fig 3F). However, the comparison of APPPS1-21-Hdac6−/− with APPPS1-21 mice revealed that target preference was significantly increased in APPPS1-21-Hdac6−/− mice (Fig 3F). In conclusion, these data suggest that that loss of Hdac6 can ameliorate associative and spatial memory impairment in a mouse model for AD.
Affiliation: Department of Psychiatry and Psychotherapy, University Medical Center, Georg-August-University Goettingen, Goettingen, Germany.