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

Abstract

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

“…Further, we show that disrupting PDE11A homodimerization is sufficient to reverse ARCD of remote social aLTMs-albeit at the expense of an inability to retrieve recent social LTMs (Figure 2). Such a transient amnesia that ultimately produces stronger remote social LTMs is also observed with genetic deletion of Pde11a in young and old adult mice [2,23].…”

“…we find that phosphorylation of PDE11A4 at serines S117 and S124 increases PDE11A4 protein expression and ectopic accumulation in filamentous structures termed "ghost axons" [2]. These agerelated increases in PDE11A protein appear to cause ARCD of social memories via the cGMP-PKG, as opposed to cAMP-PKA, pathway [2].…”

“…As described above, disrupting PDE11A4 homodimerization reduces the accumulation of PDE11A4 in punctate structures both in vivo (Figure 1F) and in vitro ( [1]; Figure 3E). Such a dispersing phenotype is also triggered in vitro by a phosphomimic mutation at S162 (i.e., S162D) [2]. As such, we sought to determine if disrupting PDE11A4 homodimerization may work by promoting phosphorylation of S162.…”

“…For instance, phosphorylation of PDE10A prevents membrane insertion by blocking palmitoylation [32]. As opposed to direct membrane insertion, PDE11A4 is thought to associate with the membrane by binding to a macromolecular complex [2]. The ability of PDE11A4 to interact with this macromolecular complex appears to be reduced when PDE11A4 homodimerization is disrupted [1] or when S162 is phosphorylated (Figure 3E), as both intramolecular signals cause PDE11A4 to shift from the membrane to the cytosol.…”

“…We aim to study the effects of healthy aging [26], therefore if upon brain dissection we had found evidence of an anatomical abnormality (e.g., a pituitary tumor), the animals would have been excluded from the study (note: no occurrences in this study Plasmid generation. Plasmids were generated as previously described [1,2]. Briefly, constructs were generated by Genscript (Piscataway, NJ) that expressed either mCherry alone, an mCherry-tagged PDE11A4-GAF-B domain (aa388-558 of NP_001074502.1,which includes 14 upstream amino acids as a spacer), EmGFP alone containing an A206Y mutation to prevent EmGFP dimerization [27], or an EmGFP-tagged mouse Pde11a4 (NM_001081033).…”