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dc.contributor.authorPilarzyk, Katy
dc.contributor.authorPorcher, Latarsha
dc.contributor.authorCapell, William R
dc.contributor.authorBurbano, Steven D
dc.contributor.authorDavis, Jeff
dc.contributor.authorFisher, Janet L
dc.contributor.authorGorny, Nicole
dc.contributor.authorPetrolle, Siena
dc.contributor.authorKelly, Michy P
dc.date.accessioned2022-09-13T12:26:29Z
dc.date.available2022-09-13T12:26:29Z
dc.date.issued2022-09-08
dc.identifier.urihttp://hdl.handle.net/10713/19720
dc.description.abstractIn 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.en_US
dc.description.urihttps://doi.org/10.1111/acel.13687en_US
dc.language.isoenen_US
dc.publisherJohn Wiley & Sonsen_US
dc.relationAll source data and uncropped original images contained in this manuscript can be found as supplementary materials.en_US
dc.relation.ispartofAging cellen_US
dc.rights© 2022 The Authors. Aging Cell published by Anatomical Society and John Wiley & Sons Ltd.en_US
dc.subjectAlzheimer's diseaseen_US
dc.subjectCOS-1en_US
dc.subjectHEK293Ten_US
dc.subjectHT-22en_US
dc.subjectSTFPen_US
dc.subjectTBIen_US
dc.subjectage-related cognitive impairmenten_US
dc.subjecthippocampusen_US
dc.subjectlearningen_US
dc.subjectmemoryen_US
dc.subjectphosphodiesteraseen_US
dc.subjectproteopathyen_US
dc.titleConserved age-related increases in hippocampal PDE11A4 cause unexpected proteinopathies and cognitive decline of social associative memories.en_US
dc.typeArticleen_US
dc.identifier.doi10.1111/acel.13687
dc.identifier.pmid36073342
dc.source.journaltitleAging cell
dc.source.beginpagee13687
dc.source.endpage
dc.source.countryUnited States
dc.source.countryUnited States
dc.source.countryUnited States
dc.source.countryEngland


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