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bioRxiv · 10.1101/2022.08.31.506102

Biologic that disrupts PDE11A4 homodimerization in hippocampus CA1 reverses age-related proteinopathies in PDE11A4 and cognitive decline of social memories

Pilarzyk, K.·Capell, W.·Rips-Goodwin, A.·Porcher, L.·Kelly, M.
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Abstract

Age-related proteinopathies in phosphodiesterase 11A (PDE11A), an enzyme that degrades 3,5-cAMP/cGMP and is enriched in the ventral hippocampal formation (VHIPP), drive age-related cognitive decline (ARCD) of social memories. In the VHIPP, age-related increases in PDE11A4 occur specifically within the membrane compartment and ectopically accumulate in filamentous structures termed ghost axons. Previous in vitro studies show that disrupting PDE11 homodimerization by expressing an isolated PDE11A-GAFB domain, which acts as a "negative sink" for monomers, selectively degrades membrane-associated PDE11A4 and prevents the punctate accumulation of PDE11A4. Therefore, we determined if disrupting PDE11A4 homodimerization in vivo via the expression of an isolated PDE11A4-GAFB domain would be sufficient to reverse 1) age-related accumulations of PDE11A4 in VHIPP ghost axons and 2) ARCD of social memories. Indeed, in vivo lentiviral expression of the isolated PDE11A4-GAFB domain in hippocampal CA1 reversed the age-related accumulation of PDE11A4 in ghost axons, reversed ACRD of social transmission of food preference memory (STFP), and improved remote long-term memory for social odor recognition (SOR) without affecting memory for non-social odor recognition. In vitro studies suggest that disrupting homodimerization of PDE11A4 does not directly alter the catalytic activity of the enzyme but may reverse age-related decreases in cGMP by dispersing the accumulation of the enzyme independently of other intramolecular mechanisms previously established to disperse PDE11A4 (e.g., phosphorylation of PDE11A4 at serine 162). Altogether, these data suggest that a biologic designed to disrupt PDE11A4 homodimerization may serve to ameliorate age-related deficits in hippocampal cyclic nucleotide signaling and subsequent ARCD of remote social memory.

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Pilarzyk, K., Capell, W., Rips-Goodwin, A., Porcher, L., Kelly, M.. 2022-09-03. Biologic that disrupts PDE11A4 homodimerization in hippocampus CA1 reverses age-related proteinopathies in PDE11A4 and cognitive decline of social memories. https://doi.org/10.1101/2022.08.31.506102

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