Proof-of-Concept and Mechanistic Studies to Repurpose Erectile Dysfunction Drugs for Elderly Females

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PROJECT SUMMARY Alzheimer’s disease (AD) is a public health crisis with no effective treatment1. Preclinical studies using a group of drugs—commonly termed "PDE5A inhibitors”, which include tadalafil, vardenafil and sildenafil—have shown that the suppression of the enzyme phosphodiesterase 5A (PDE5A) can improve memory in mice prone to AD. This begs the question whether these drugs, currently in clinical use for erectile dysfunction and pulmonary artery hypertension, can be repurposed for AD patients. Such an approach would merit a thorough investigation into the mechanism of action of PDE5A inhibitors on brain function. Complexities however arise from the fact that the structurally–related enzyme PDE11A is also expressed abundantly in various AD– vulnerable brain regions, such as the cortex and hippocampus, and that tadalafil potently inhibits PDE11A, albeit with a 7–fold higher IC50 compared with PDE5A. It is therefore imperative that we (a) tease apart the relative effects of inhibiting PDE5A and PDE11A on cognitive loss, and (b) determine whether PDE11A is itself an actionable target. Towards these goals, we will first map the expression of Pde5a and Pde11a transcripts using qPCR, RNAscope and immunohistochemistry in various brain regions and sub–regions of aged mice and 3xTg mice (Specific Aim 1). We will then inject CRISPR constructs for Pde5a and Pde11a stereotactically into the hippocampus of 3xTg mice to determine whether PDE5A and/or PDE11A inhibition prevent cognitive decline, measured by the Novel Object Recognition and Morris Water Maze tests, and amyloidogenic protein accumulation (Specific Aim 2). Consistent with the goals of the Administrative Supplement under PA–20–272, NOT–AG–22–025, this 1–year project will yield preliminary data towards a new R01 application to fully study a role for PDE5A and PDE11A in brain function.