Functional Effects of PDE11A Alzheimer's-Associated Variants

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PROJECT SUMMARY: Functional Effects of PDE11A Alzheimer’s Disease (AD)-Associated Variants This parent grant explores how age-related increases in expression and ectopic localization of the enzyme Phosphodiesterase 11A (PDE11A) drive age-related cognitive decline (ARCD). PDE11A is of particular interest in the context of aging and AD because its expression in brain is enriched in the hippocampal formation—a region that is critical for episodic memory and is severely impaired in AD. We find PDE11A expression increases with age in the rodent and human hippocampus and is further elevated in hippocampus of demented vs. non-demented aged humans with a history of TBI. We have established that these age-related increases in PDE11A are ectopically enriched in hippocampal “ghost axons”—that is, axonal terminals that are so densely packed with PDE11A protein that other axonal proteins are occluded. Through mutational analyses, we have identified intramolecular signals responsible for these age-related increases in PDE11A expression and its ectopic localization and have shown that Pde11a knockout mice are protected against ARCD. Given that advanced age is the strongest risk factor for dementia, coupled with the fact that these PDE11A “ghost axons” are particularly reminiscent of tau proteinopathies that are associated with ADRDs, it is highly interesting that 2 rare PDE11A variants (i.e., R202H and L756Q) have recently been associated with early-onset AD. The impact of these mutations on PDE11A function were not measured directly; however, expression of the mutants increased phosphorylation of recombinant tau in an in vitro assay. This PDE11A mutation-induced increase in p-tau is consistent with the pathophysiology observed in ADRD brains; however, it suggests a PDE11A loss-of- function that stands in direct contrast to the PDE11A gain-of-function that we observe with normal aging. As such, we test the overarching hypothesis that AD-related PDE11A mutations alter catalytic activity and/or subcellular compartmentalization of PDE11A in a manner that fundamentally differs from aging itself, thereby producing biochemical and behavioral deficits worse than those seen with normal aging. Across the 2 aims, we take an integrative approach by coupling in vivo and in vitro genetic manipulations with behavioral, physiological, and biochemical endpoints. In Specific Aim 1, we determine how the AD-related PDE11A variants alter protein expression, catalytic activity, subcellular compartmentalization, phosphorylation, and downstream signaling of PDE11A in a hippocampal cell line that endogenously expresses tau and recapitulates PDE11A age-related proteinopathies. In Specific Aim 2, we determine if elevated expression of these PDE11A AD-associated variants in mouse hippocampus produces more widespread cognitive decline than elevated expression of wild-type PDE11A.These innovative studies will provide much needed insight into the functional consequences of these AD-related mutations and are consistent with the Division of Neuroscience’s goal to understand how the processes of ARCD intersect with the development of AD.