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

> **NIH NIH RF1** · UNIVERSITY OF SOUTHERN CALIFORNIA · 2022 · $2,417,667

## 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. And, 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. The overall goal of
this project is to test the hypothesis that cPLA2 activation is associated with faster cognitive
decline in APOE4 carriers by accelerating brain inflammation and AD and vascular pathology.
Leveraging brain biospecimens and detailed clinical and neuropathological data from the
Religious Order Study (ROS) cohort, we propose the following three Aims. In Aim 1, we will
examine the patterns of cPLA2 activation and signaling pathways in older subjects across a range
of cognitive function, 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 cognitive function. In Aim 3, we will investigate whether the association between
the prodromal decline in global cognitive and APOE genotype is mediated by cPLA2 activation.
In addition, we will explore if inflammation, 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.

## Key facts

- **NIH application ID:** 10464564
- **Project number:** 1RF1AG076124-01A1
- **Recipient organization:** UNIVERSITY OF SOUTHERN CALIFORNIA
- **Principal Investigator:** Zoe Arvanitakis
- **Activity code:** RF1 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $2,417,667
- **Award type:** 1
- **Project period:** 2022-05-15 → 2025-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10464564

## Citation

> US National Institutes of Health, RePORTER application 10464564, Brain cPLA2 as a mechanism for neuroinflammation in AD/ADRD with and without APOE4 (1RF1AG076124-01A1). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10464564. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*