# Activation of Soluble Adenylyl Cyclase as a Novel Therapeutic Strategy for the Treatment of Age-Related Neurodegenerative Disorders

> **NIH NIH F31** · WEILL MEDICAL COLL OF CORNELL UNIV · 2022 · $37,439

## Abstract

Project Summary/Abstract
 The worldwide population of individuals over the age of 65 is continuing to grow and is expected to double
over the next 30 years. Due to this increase, an associated rise in age-related neurodegenerative diseases
(NDs), such as Alzheimer’s (AD) and Parkinson’s disease, has been observed. Despite decades of research,
there are currently no FDA-approved therapies that can stop or reverse disease progression. The accumulation
of misfolded protein aggregates is a common feature of age-related NDs and is thought to be heavily involved
in the pathophysiology of the diseases. Proteins aggregates can be cleared from the cell through autophagy,
one of the major biological degradation pathways. Protein aggregates are degraded in the final step of
autophagy, where they are delivered to cellular organelles known as lysosomes. Lysosomes maintain an acidic
pH between 4-5 to maintain an optimal environment for acid hydrolases. In aging cells and in a cellular model of
AD, lysosomes become less acidic, their hydrolases become less active and, as a result, there is a decrease in
degradation through autophagy (i.e., autophagic flux) and an accumulation of undigested materials. In models
of AD pathology, re-acidification of lysosomal pH, via addition of exogenous cAMP, reversed this phenotype. In
line with these findings, we have shown that cAMP generated from a cytosolic adenylyl cyclase isoform, known
as Soluble Adenylyl Cyclase (sAC), promotes lysosomal acidification. In addition, cells that do not express sAC
show decreased autophagic flux. This, and other, physiological roles of sAC have been determined via the use
of inhibitors and various genetic tools that were developed to study sAC biology. However, the “toolbox” that is
currently used to study sAC is lacking a key component: a pharmacological activator of sAC. To identify a sAC
activator, we conducted a high-throughput screen of 400,000 chemically diverse compounds. From this library
we discovered 13 presumptive sAC activators. In this proposal, I describe the in vitro and cell-based assays that
I will use to confirm, characterize, and further develop these 13 compounds as “first-of-their kind” small molecule
activators selective for sAC. Using the newly discovered sAC activators, I will test the hypothesis that stimulating
sAC can enhance lysosomal acidification and stimulate autophagy, and as a result, decrease accumulation of
protein aggregates. If successful, these studies will validate small molecule sAC activators as a potential novel
therapeutic strategy to treat neurodegenerative disorders.

## Key facts

- **NIH application ID:** 10443843
- **Project number:** 5F31AG069501-03
- **Recipient organization:** WEILL MEDICAL COLL OF CORNELL UNIV
- **Principal Investigator:** Thomas Rossetti
- **Activity code:** F31 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $37,439
- **Award type:** 5
- **Project period:** 2020-08-11 → 2023-02-28

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10443843

## Citation

> US National Institutes of Health, RePORTER application 10443843, Activation of Soluble Adenylyl Cyclase as a Novel Therapeutic Strategy for the Treatment of Age-Related Neurodegenerative Disorders (5F31AG069501-03). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10443843. Licensed CC0.

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