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

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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.