# MicroRNA Regulation of Phospholipid Homeostasis in Alzheimer's Disease Pathogenesis > **NIH VA I01** · JAMES J PETERS VA MEDICAL CENTER · 2022 · — ## Abstract PROJECT SUMMARY APOE4 is the strongest genetic risk factor for sporadic AD with Ab-dependent and Ab-independent effects on disease pathogenesis. However, the molecular mechanisms underlying the pathogenic nature of APOE4 in AD are not fully elucidated. In previous funding period (07/01/2017-present), we have made significant progress toward understanding micro-RNA (miRNA) regulation of APOE4-induced brain phospholipid dysregulation in AD. We have uncovered a novel regulatory mechanism of miR-195 targeted at APOE4-associated cognitive deficits and lysosomal defects in AD. Notably, we identified miR-195 as a top miRNA candidate involved in the APOE- regulated brain phosphoinositol biphosphate (PIP2) pathway using human ROSMAP and mouse microarray data. Levels of miR-195 are significantly lower in APOE4+ human and mouse brains, and in human inducible pluripotent stem cells (iPSC)-derived neurons and astrocytes when compared to APOE4- counterparts. Over- expressing miR-195 reduces expression levels of its top target synaptojanin 1 (synj1), the brain PIP2 degrading enzyme. Elevating miR-195 ameliorates cognitive deficits and AD pathology in APOE4+ mice and rescues lysosomal defects in APOE4+ iPSC brain cells. Furthermore, our preliminary results support the role of miR-195 as an anti-inflammatory miRNA in regulating microglial function. Our single cell (sc)-RNA seq. analysis of E4FAD mouse brains with miR-195 over-expression suggests that miR-195 alters molecular signatures of microglia sub- clusters. APOE4+ microglia with lower miR-195 levels and higher synj1 expression at baseline, manifests with impaired phagocytic activities and lysosomal defects when compared to APOE3+ microglia. Down-regulation of synj1 or over-expression of miR-195 can rescue these phenotypes. Beside synj1, inflammatory genes pdcd4 and smad7 are predicted targets of miR-195 as well. Over-expression of miR-195 in microglia inhibits lipopolysaccharide (LPS)-induced increases in smad7 and pdcd4 expression, attenuates LPS-induced proinflammatory cytokine release and augments anti-inflammatory responses. In addition, exosomes derived from APOE4/4 astrocytes (ADEs) contain less miR-195 than those in APOE3/3 ADEs, and over-expression of miR-195 in APOE4/4 astrocytes increases miR-195 levels in ADEs which can attenuate LPS-induced pro- inflammatory cytokine release. Therefore, we hypothesize that miR-195 may exhibit anti-inflammatory effects through down-regulation of microglial synj1 to regulate lysosomal function, direct target at microglial inflammatory gene expression and responses, and modulation of neuro-inflammation and tau spread by exosomal miR-195. We propose to characterize the regulation of microglial function by miR-195 during AD pathogenesis in this renewal application. We will: 1) determine the impact of miR-195 on microglia function and APOE-regulated neuro-inflammation in AD in vivo (Aim 1) using cuprizone (CPZ)-induced inflammation in male and female EFAD mouse models... ## Key facts - **NIH application ID:** 10368318 - **Project number:** 2I01BX003380-05 - **Recipient organization:** JAMES J PETERS VA MEDICAL CENTER - **Principal Investigator:** Dongming Cai - **Activity code:** I01 (R01, R21, SBIR, etc.) - **Funding institute:** VA - **Fiscal year:** 2022 - **Award amount:** — - **Award type:** 2 - **Project period:** 2017-07-01 → 2025-12-31 ## Primary source NIH RePORTER: https://reporter.nih.gov/project-details/10368318 ## Citation > US National Institutes of Health, RePORTER application 10368318, MicroRNA Regulation of Phospholipid Homeostasis in Alzheimer's Disease Pathogenesis (2I01BX003380-05). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10368318. Licensed CC0. --- *[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*