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    Conserved age-related increases in hippocampal PDE11A4 cause unexpected proteinopathies and cognitive decline of social associative memories.

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    Author
    Pilarzyk, Katy
    Porcher, Latarsha
    Capell, William R
    Burbano, Steven D
    Davis, Jeff
    Fisher, Janet L
    Gorny, Nicole
    Petrolle, Siena
    Kelly, Michy P
    Date
    2022-09-08
    Journal
    Aging cell
    Publisher
    John Wiley & Sons
    Type
    Article
    
    Metadata
    Show full item record
    See at
    https://doi.org/10.1111/acel.13687
    Abstract
    In humans, associative memories are more susceptible to age-related cognitive decline (ARCD) than are recognition memories. Reduced cAMP/cGMP signaling in the hippocampus may contribute to ARCD. Here, we found that both aging and traumatic brain injury-associated dementia increased the expression of the cAMP/cGMP-degrading enzyme phosphodiesterase 11A (PDE11A) in the human hippocampus. Further, age-related increases in hippocampal PDE11A4 mRNA and protein were conserved in mice, as was the increased vulnerability of associative versus recognition memories to ARCD. Interestingly, mouse PDE11A4 protein in the aged ventral hippocampus (VHIPP) ectopically accumulated in the membrane fraction and filamentous structures we term “ghost axons.” These age-related increases in expression were driven by reduced exoribonuclease-mediated degradation of PDE11A mRNA and increased PDE11A4-pS117/pS124, the latter of which also drove the punctate accumulation of PDE11A4. In contrast, PDE11A4-pS162 caused dispersal. Importantly, preventing age-related increases in PDE11 expression via genetic deletion protected mice from ARCD of short-term and remote long-term associative memory (aLTM) in the social transmission of food preference assay, albeit at the expense of recent aLTM. Further, mimicking age-related overexpression of PDE11A4 in CA1 of old KO mice caused aging-like impairments in CREB function and remote social—but not non-social—LTMs. RNA sequencing and phosphoproteomic analyses of VHIPP identified cGMP-PKG—as opposed to cAMP-PKA—as well as circadian entrainment, glutamatergic/cholinergic synapses, calcium signaling, oxytocin, and retrograde endocannabinoid signaling as mechanisms by which PDE11A deletion protects against ARCD. Together, these data suggest that PDE11A4 proteinopathies acutely impair signaling in the aged brain and contribute to ARCD of social memories.
    Data Availibility
    All source data and uncropped original images contained in this manuscript can be found as supplementary materials.
    Rights/Terms
    © 2022 The Authors. Aging Cell published by Anatomical Society and John Wiley & Sons Ltd.
    Keyword
    Alzheimer's disease
    COS-1
    HEK293T
    HT-22
    STFP
    TBI
    age-related cognitive impairment
    hippocampus
    learning
    memory
    phosphodiesterase
    proteopathy
    Show allShow less
    Identifier to cite or link to this item
    http://hdl.handle.net/10713/19720
    ae974a485f413a2113503eed53cd6c53
    10.1111/acel.13687
    Scopus Count
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