# MicroRNA Regulation of Phospholipid Homeostasis in Alzheimer's Disease Pathogenesis

> **NIH VA I01** · JAMES J PETERS VA  MEDICAL CENTER · 2020 · —

## Abstract

Background The ApoE4 genotype is the strongest genetic risk factor for developing AD. However, the
mechanisms that underlie this link between ApoE4 genotype and SAD are not well understood.
Objective/Hypothesis The objectives are to understand the molecular underpinnings of the association
between ApoE4-specific changes in miRNA profile and ApoE4-induced brain phospholipid dysregulation which
leads to ApoE4 increased susceptibility to develop SAD. Our recent findings demonstrate that ApoE proteins
are critical determinants of brain phospholipid homeostasis and that the ApoE4 isoform is dysfunctional in this
process. We have found that the levels of PIP2 are reduced in human and mouse brains of ApoE4 carriers, and
in primary neurons expressing ApoE4 alleles when compared to those levels in ApoE3 counterparts. These
changes are secondary to increased expression of a PIP2 degrading enzyme, the phosphoinositol phosphatase
synaptojanin 1 (synj1), in ApoE4 carriers. Genetic reduction of synj1 in ApoE4 mice restores PIP2 levels and
more importantly, rescues AD-related cognitive deficits. These findings are the first to link synj1 and PIP2
homeostasis to the pathogenic effects of ApoE4 in sporadic AD. Further studies suggest that ApoE4 behaves
like the ApoE null conditions, which fails to degrade synj1 mRNA efficiently unlike ApoE3 does. We have also
found that the levels of miR195 and miR374 are significantly lowered in ApoE4 mouse (9-12 months of age)
and human brains (MCI and early AD subjects) compared to those in non-ApoE4 counterparts. Over-
expression of miR195 but not miR374 in ApoE4 treated neurons reduces synj1 protein expression. Moreover,
we have found that disruption of ApoE binding to its receptors LRP1 or genetic knockdown of LRP1 abolishes
ApoE-induced changes in miR195/synj1 pathways. Therefore, we hypothesize that ApoE3 binds to LRP1 to
up-regulate miR195 expression which subsequently modulates synj1 mRNA degradation rate and synj1
expression levels in the brain. In ApoE4 neurons and brains, decreased levels of miR195 may contribute to the
reduced degradation rate of synj1 mRNA, thereby increasing synj1 protein expression and reduce brain PIP2
levels. These changes may contribute to ApoE4-associated synaptic and cognitive dysfunction.
Rationale/Experimental Design In this application, we will study the effects of specific miRNA changes on
ApoE4-associated phospholipid dyshomeostasis, synaptic dysfunction as well as cognitive dysfunction (aim 1).
We will determine if elevating miR195 (which are low in ApoE4 mouse brains when compared to ApoE3
counterparts) by intraventricular injection of viral-containing miRNAs, can correct phospholipid
dyshomeostasis, and rescue synaptic and cognitive deficits in ApoE4 mice without and with AD transgenic
background in vivo. We will also determine if inhibiting miR195 by antagomirs in ApoE3 mouse brains without
AD transgenic background can result in phospholipid dysregulation and subsequent synaptic and...

## Key facts

- **NIH application ID:** 9932273
- **Project number:** 5I01BX003380-04
- **Recipient organization:** JAMES J PETERS VA  MEDICAL CENTER
- **Principal Investigator:** Dongming Cai
- **Activity code:** I01 (R01, R21, SBIR, etc.)
- **Funding institute:** VA
- **Fiscal year:** 2020
- **Award amount:** —
- **Award type:** 5
- **Project period:** 2017-07-01 → 2021-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9932273

## Citation

> US National Institutes of Health, RePORTER application 9932273, MicroRNA Regulation of Phospholipid Homeostasis in Alzheimer's Disease Pathogenesis (5I01BX003380-04). Retrieved via AI Analytics 2026-06-05 from https://api.ai-analytics.org/grant/nih/9932273. Licensed CC0.

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