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Aims: Alzheimer'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. Methods: The 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. Results: We showed that calmodulin (CaM) acetylation is reduced in plasma of AD patients and mice. CaM acetylation and its target Ca2+/CaM‐dependent kinase II α (CaMKIIα) 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 CaMKIIα activity, and hippocampus‐dependent memory in AD mice. Conclusions: HDAC9‐mediated CaM deacetylation induces memory impairment in AD, HDAC9, or CaM acetylation may become potential therapeutic targets for AD. [ABSTRACT FROM AUTHOR]

Understanding mechanisms governing the trafficking of transmembrane (TM) cargoes to synapses and other specialized membranes in neurons represents a long-standing challenge in cell biology. Investigation of the neuron-enriched endosomal protein of 21 kDa (NEEP21, or NSG1or P21) and Calcyon (Caly, or NSG3) indicates that the emergence of the NEEP21/Caly/P19 gene family could play a vital role in the success of these mechanisms in vertebrates. The upshot of a sizeable body of work is that the NEEP21 and Caly perform distinct endocytic and recycling functions, which impact (i) α amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid-type glutamate receptor trafficking at excitatory synapses; (ii) transport to/in neuronal axons; as well as (iii) proteolytic processing of amyloid precursor protein and neuregulin 1, suggesting roles in neuron development, synaptic function, and neurodegeneration. We argue that their distinct effects on cargo endocytosis and recycling depend on interactions with vesicle trafficking and synaptic scaffolding proteins. As they play complementary, but opposing roles in cargo endocytosis, recycling, and degradation, balancing NEEP21 and Caly expression levels or activity could be important for homeostasis in a variety of signaling pathways, and also lead to a novel therapeutic strategy for disorders like Alzheimer's disease and schizophrenia. [ABSTRACT FROM AUTHOR]