HDAC9-mediated calmodulin deacetylation induces memory impairment in Alzheimer's disease

AimsAlzheimer's disease (AD) is a neurodegenerative disease characterized by progressive cognitive dysfunction and memory impairment. AD pathology involves protein acetylation. Previous studies have mainly focused on histone acetylation in AD, however, the roles of nonhistone acetylation in AD are less explored.MethodsThe protein acetylation and expression levels were detected by western blotting and co-immunoprecipitation. The stoichiometry of acetylation was measured by home-made and site-specific antibodies against acetylated-CaM (Ac-CaM) at K22, K95, and K116. Hippocampus-dependent learning and memory were evaluated by using the Morris water maze, novel object recognition, and contextual fear conditioning tests.ResultsWe showed that calmodulin (CaM) acetylation is reduced in plasma of AD patients and mice. CaM acetylation and its target Ca2+/CaM-dependent kinase II alpha (CaMKII alpha) activity were severely impaired in AD mouse brain. The stoichiometry showed that Ac-K22, K95-CaM acetylation were decreased in AD patients and mice. Moreover, we screened and identified that lysine deacetylase 9 (HDAC9) was the main deacetylase for CaM. In addition, HDAC9 inhibition increased CaM acetylation and CaMKII alpha activity, and hippocampus-dependent memory in AD mice.ConclusionsHDAC9-mediated CaM deacetylation induces memory impairment in AD, HDAC9, or CaM acetylation may become potential therapeutic targets for AD. HDAC9 is the CaM deacetylase, which is upregulated in APP/PS1 mouse forebrain neurons, causing CaM hyperdeacetylation. The latter impairs CaMKII alpha activity and memory in APP/PS1 mice. HDAC9 inhibition enhances CaMKII alpha activity via increasing CaM acetylation, thus improving the memory deficits of APP/PS1 mice.image