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Knockdown of heterochromatin protein 1 binding protein 3 recapitulates phenotypic, cellular, and molecular features of aging [RNA-Seq]

ABSTRACT: Identifying genetic factors that modify an individual’s 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 Alzheimer’s 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.

ORGANISM(S): Mus musculus

PROVIDER: GSE119318 | GEO | 2018/12/14

REPOSITORIES: GEO

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Project description:The decline of cognitive function is a feature of normal human aging and is exacerbated in AlzheimerM-bM-^@M-^Ys disease (AD). DNA repair declines in brain cells during normal aging and even more so in AD. Here we show that experimental reduction in levels of the base excision repair enzyme, DNA polymerase M-NM-2 (Polb) renders neurons vulnerable to age-related dysfunction and degeneration in a mouse model of AD. Whereas 3xTgAD mice exhibit age-related extracellular amyloid b-peptide (Ab) accumulation and cognitive deficits, but no neuronal death, 3xTg/Polb+/- mice accumulates intracellular Ab and neurons die in the hippocampus and cerebral cortex. The DNA repair-deficient 3xTgAD mice exhibited increased DNA strand breaks and apoptotic caspase activation with loss of hippocampal volume, and impaired synaptic plasticity and memory retention. Molecular profiling revealed remarkable similarities in gene expression alterations in brain cells of AD patients and 3xTgAD/Polb+/- mice including multiple abnormalities suggestive of impaired cellular bioenergetics. Our findings demonstrate that a modest decrement in oxidative DNA damage processing is sufficient to render neurons vulnerable to AD-related pathogenic molecular and cellular alterations that result in the dysfunction and death of neurons, and associated cognitive deficits. 4 mouse strains were used in these experiments, the 3xTgAD and Pol M-NM-2 (+/-) mice were bred at the National Institute on Aging (Baltimore, Maryland). The original line 3xTgAD line was generated as described previously (Oddo, et. al 2003) and possess APPswe, PS1M146V, and tauP301L mutations. DNA polymerase beta heterozygous mice, Pol M-NM-2 (+/-), were crossed with the 3xTgAD mice to generate a 3xTgAD/Pol M-NM-2 (+/-) mouse. The Wt strain is C57Bl/6. At 20 months of age these mice were euthanized by cervical dislocation, the brain removed from the skull and dissected into regions of interest, the prefrontal cortex was used for the microarray studies.

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Knockdown of heterochromatin protein 1 binding protein 3 recapitulates phenotypic, cellular, and molecular features of aging [RNA-Seq]

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