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Learn MoreIdentifying genetic factors that modify an individuals susceptibility to cognitive decline in aging is critical to understanding biological processes involved and mitigating risk associated with a number of age-related disorders. Recently, heterochromatin protein 1 binding protein 3 (Hp1bp3) was identified as a mediator of cognitive aging. Here we provide a mechanistic explanation for these findings and show that targeted knockdown of Hp1bp3 in the hippocampus by 50-75% is sufficient to induce cognitive deficits and transcriptional changes reminiscent of those observed in aging and Alzheimers disease brains. Specifically, neuroinflammatory-related pathways become activated following Hp1bp3 KD in combination with a robust decrease in genes involved in synaptic activity and neuronal function. To test the hypothesis that Hp1bp3 mediates susceptibility to cognitive deficits via a role in neuronal excitability, we performed slice electrophysiology demonstrate transcriptional changes after Hp1bp3 KD manifest functionally as a reduction in hippocampal neuronal intrinsic excitability and synaptic plasticity. In addition, as Hp1bp3 is a known mediator of miRNA biogenesis, here we profile the miRNA transcriptome and identify mir-223 as a putative regulator of a portion of observed mRNA changes, particularly those that are inflammatory-related. In summary, work here identifies Hp1bp3 as a critical mediator of aging-related changes at the phenotypic, cellular, and molecular level and will help inform the development of therapeutics designed to target either Hp1bp3 or its downstream effectors in order to promote cognitive longevity. SOURCE: Catherine,C,Kaczorowski (catherine.kaczorowski@jax.org) - The Jackson Laboratory
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