# Brain cPLA2 as a mechanism for neuroinflammation in AD/ADRD with and without APOE4 Diversity Supplement

> **NIH NIH RF1** · UNIVERSITY OF SOUTHERN CALIFORNIA · 2024 · $75,593

## Abstract

ABSTRACT: The elucidation of potentially modifiable molecular pathways involved in
Alzheimer’s disease (AD)/Alzheimer’s Disease Related Dementia (ADRD) is of great scientific
interest and offers hope for improved public health. Mounting evidence points to the role of
calcium-dependent phospholipase A2 (cPLA2) in ADRD. Indeed, cPLA2 expression is
increased around amyloid plaques in patients with AD and is associated with a brain
inflammatory response. Reducing cPLA2 gene expression improves learning and memory in AD
mouse models. Further, APOE4, the strongest genetic risk factor for late-onset AD, has been
shown to promote and accelerate brain inflammation, while the underlying mechanisms are not
well understood. This project aims to test the hypothesis that cPLA2 activation is associated
with faster cognitive decline in APOE4 carriers by accelerating known pathology (AD and
vascular) and brain inflammation. Leveraging brain biospecimens and detailed clinical and
neuropathological data from the Religious Order Study cohort, we propose the following three
Aims. In Aim 1, we will examine the patterns of cPLA2 activation and signaling pathways in
older subjects with and without dementia (clinical AD), stratified by APOE4 using frozen human
brain samples and single brain cell types isolated from a subset of samples. In Aim 2, we will
use ex vivo stimulation to study cPLA2 activation and signaling mechanisms in neurons and glia
of post-mortem brain tissues, stratified by APOE4 and dementia. In Aim 3, we will investigate
whether the association between the decline in global cognitive and APOE genotype is
mediated by cPLA2 activation. In addition, we will explore if AD neuropathological markers (Aβ,
pTau, or both) and other vascular pathological markers mediate this association. This project
will elucidate a novel mechanism for APOE4 induced brain inflammation in AD/ADRD. The
study of available brain tissues from well-characterized autopsied persons with a range of
clinical and pathologic phenotypes will provide deep insights into cell-specific cPLA2 activation
profiles in relation to APOE4 and markers of inflammation. Identifying a role for cPLA2 activation
in AD inflammation is a significant step toward the development of cPLA2 inhibitors, and
ultimately improved treatments for AD/ADRD. The focus of this supplement plan will be to
expand on cPLA2 research by studying it in the context of cellular senescence with two
particular aims: AIM 1: Identify whether cPLA2 is required for lipid-induced senescence in iPSC-
derived astrocytes. And, AIM 2: Assess senescence phenotypes in a patient-derived-iPSC
population.

## Key facts

- **NIH application ID:** 11080137
- **Project number:** 3RF1AG076124-01A1S1
- **Recipient organization:** UNIVERSITY OF SOUTHERN CALIFORNIA
- **Principal Investigator:** Zoe Arvanitakis
- **Activity code:** RF1 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $75,593
- **Award type:** 3
- **Project period:** 2022-05-15 → 2025-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/11080137

## Citation

> US National Institutes of Health, RePORTER application 11080137, Brain cPLA2 as a mechanism for neuroinflammation in AD/ADRD with and without APOE4 Diversity Supplement (3RF1AG076124-01A1S1). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/11080137. Licensed CC0.

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