# Novel regulation of autophagic flux for the treatment of Alzheimer's disease

> **NIH NIH R43** · CERACUITY, INC. · 2022 · $499,272

## Abstract

PROJECT SUMMARY
Alzheimer’s Disease (AD) is a progressive neurodegenerative disease that leads to cognitive decline. According
to the WHO (2020), AD affects 30 million people worldwide. This number is expected to triple by 2050, with an
annual forecasted global cost of over $600 billion. Currently, no disease-modifying treatments are available and
no new AD therapeutics have been approved by the FDA in over 15 years. AD is characterized in part by the
accumulation of phosphorylated tau proteins. Despite promising preclinical data, therapeutics targeting tau
accumulation have not shown clinical efficacy. Autophagy is a multistep process that facilitates the removal of
aggregated proteins and is essential to prevent neurodegeneration. This clearance of proteins is termed
autophagic flux. AD is characterized by aberrant accumulation of endogenous proteins, specifically tau
accumulation into intracellular neurofibrillary tangles. AD brains show neuronal accumulation of autophagic
vacuoles indicating that while autophagosomes form and envelop proteinopathies, they are not efficiently
cleared. The autophagic flux pathway becomes less efficient with aging and disease stage whereby,
autophagosome maturation and autolysosome clearance are critically impaired. In neurodegenerative diseases,
this can result in the retention of proteotoxic substrates like hyperphosphorylated and aggregated tau. These
observations support the targeting of dysfunctional autophagic flux as a therapeutic approach for AD. PLD1 is
an inducible, lipolytic phosphodiesterase enzyme that preferentially colocalizes with autophagosomes and is
involved in the maturation of autophagosomes to autolysosomes, which is the final step of autophagy. In
organotypic brain slices from mice, PLD1 inhibition results in higher levels of insoluble hyperphosphorylated tau
and p62 aggregates, a protein primarily degraded via autophagy. These data suggest PLD1 is a promising
therapeutic target for AD with benefits in promoting autophagic flux and neuronal health. Ceracuity is developing
a novel series of PLD1 activator compounds to promote autophagic flux in neurons and clearance of tau
aggregates. Ceracuity’s approach offers a number of advantages over other means to enhance autophagic flux
as a strategy to treat AD, such as the ability of the autophagy-lysosome pathway to clear large, oligomerized
proteins found in AD, and the ability of PLD1 activators to increase the clearance of tau aggregates by
upregulating autophagic flux. To achieve these goals, Ceracuity will identify and rank new chemistry starting
points to diversify the pool of lead candidates from a library of ~150K compounds, and then define the in vivo
efficacy of the top hit compounds in a tau mutant zebrafish model.

## Key facts

- **NIH application ID:** 10381804
- **Project number:** 1R43AG076052-01
- **Recipient organization:** CERACUITY, INC.
- **Principal Investigator:** William J Greenlee
- **Activity code:** R43 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $499,272
- **Award type:** 1
- **Project period:** 2022-09-15 → 2024-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10381804

## Citation

> US National Institutes of Health, RePORTER application 10381804, Novel regulation of autophagic flux for the treatment of Alzheimer's disease (1R43AG076052-01). Retrieved via AI Analytics 2026-06-01 from https://api.ai-analytics.org/grant/nih/10381804. Licensed CC0.

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