# Discovery of allosteric activators of phospholipase C-gamma2 to treat Alzheimer's disease

> **NIH NIH R56** · UNIV OF NORTH CAROLINA CHAPEL HILL · 2024 · $748,573

## Abstract

ABSTRACT
 Current therapies for Alzheimer’s disease (AD) do not reverse, or even slow, progression of the disease.
This situation is dire and exacerbated by the failure of antibodies directed toward two of the more promising
targets—phosphorylated tau and beta-amyloids—to treat the disease. Clearly, new treatments are urgently
needed.
 In 2017, a large genome-wide study associated a naturally-occurring variant (P522R) of PLCG2, the gene
encoding PLC-2, with protection from late onset AD. In follow-up studies, this genetic association has remained
strong and highly reproducible. Even more encouraging, in clinical studies of patients with mild cognitive
impairment, people that carried PLCG2 (P522R) had slower rates of cognitive decline compared to non-carriers.
Protection was observed even for patients homozygous for ApoE4, a biomarker strongly linked to AD. In the
brain, PLC-2 is primarily expressed in microglial cells where it controls phagocytic and neuroinflammatory
processes. It is more highly expressed in pathological areas of patients with AD. In microglia, PLC-2 is activated
downstream of both TREM2 (which uses ApoE4 as a ligand) and CSF1R, two transmembrane receptors that
are strongly linked to AD. Similarly, PLC-2 activates PKC, which is also linked to AD. Thus, genetic and cellular
data strongly support PLC-2 as a novel therapeutic target for treatment of AD.
 The phospholipase activity of PLC-2 (P522R) is modestly elevated relative to its wild-type counterpart and
it is this increased activity in microglia that is generally accepted to protect against AD. We propose to identify
and optimize small molecules that selectively activate PLC-2 to reproduce the neuroprotective effects of PLC-
2 (P522R) and treat AD. The research plan relies on complementary high-throughput assays enabled by two
fluorogenic substrates for eukaryotic PLCs that we invented explicitly for this research. Consequently, we will
pursue three Aims. In Aim 1, in-house collections totaling ~300,000 compounds will be screened for activators
of PLC-2 and primary hits verified for activity, selectivity, composition, and purity; cheminformatics will be used
to structurally classify hits. In Aim 2, a high-quality model of full-length PLC-2 coupled with molecular dynamics
simulations will be used for computational screens of tens of millions of compounds. In Aim 3, a suite of
biochemical, biophysical, and cell biological studies will be used to prioritize allosteric activators of PLC-2 with
favorable chemical and pharmacological properties. These novel small molecules will be invaluable tools to
further understand how PLC-2 (P522R) reduces the risk of AD. The small molecules will also be used as leads
for the development of novel therapeutics to treat AD.

## Key facts

- **NIH application ID:** 10916558
- **Project number:** 5R56AG083424-02
- **Recipient organization:** UNIV OF NORTH CAROLINA CHAPEL HILL
- **Principal Investigator:** Kenneth Hugh Pearce
- **Activity code:** R56 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $748,573
- **Award type:** 5
- **Project period:** 2023-09-01 → 2026-02-28

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10916558

## Citation

> US National Institutes of Health, RePORTER application 10916558, Discovery of allosteric activators of phospholipase C-gamma2 to treat Alzheimer's disease (5R56AG083424-02). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10916558. Licensed CC0.

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