# A Role of Astrocyte and Microglia Interplay in Alzheimer's Disease

> **NIH NIH K99** · SANFORD BURNHAM PREBYS MEDICAL DISCOVERY INSTITUTE · 2022 · $131,298

## Abstract

Project Summary/Abstract
Alzheimer’s disease (AD) is the most common neurodegenerative disease affecting over 3 million Americans
yearly, with extracellular accumulation of β-amyloid and intracellular tau aggregates, and aberrant glial activation
pathologies. Glial dysfunction can trigger excitotoxicity and neuroinflammation, which is invariably involved in
AD pathogenesis. However, how astrocyte and microglia become reactive in the pathogenesis of AD is not clear.
Previously, I have identified a novel ER component, membralin (TMEM259), as an important disease modifier in
the pathogenesis of AD and Amytrophic Lateral Sclerosis (ALS). First, I find that membralin can modulate the
integrity and activity of the γ-secretase complex. I found that knocking down of membralin expression in a mouse
model of AD (TgCRND8) can exacerbated Aβ pathology and memory impairment. More recently, I have identified
a non-cell-autonomous glutamate clearance mechanism in astrocytes mediated by membralin through regulation
of the glutamate transporter, EAAT2. Elevation of membralin through AAV virus injection can significantly
increase EAAT2 levels and extend the lifespan of the SOD1G93A ALS mice. Interestingly, astrocyte-deletion of
membralin can lead a severe neuroinflammatory pathologies, as shown by remarkable elevation of gliosis
markers: GFAP (astrocytes), IBA1 and CD68 (microglia). Transcriptomic analysis of astrocyte conditional
knockout animals confirms the upregulation of genes associated to gliosis, neuroinflammation and abnormal
immune response. I found reduced membralin levels in brain samples from both AD and ALS patients.
Excitotoxicity, EAAT2 dysfunction and gliosis are common pathological features in AD and ALS. Moreover, a
recent genome-wide association (GWAS) study has shown that the membralin gene locus (also known as
C19ORF6 in human) is located within 500 bp of a single nucleotide polymorphism (SNP, rs117481827) tightly
associated with late-onset AD, and splicing of membralin transcripts has been reported to be significantly altered
in AD. Thus, I hypothesize that upregulation of astrocytic membralin pathways can attenuate glutamate
excitotoxicity and modulate microglial-dependent pathogenic effects in AD.
In the K99 phase of this study, I will characterize molecular mechanisms underlying membralin-associated
astrocyte function and dissect the induction mechanisms of reactive astrocytes (Aim 1). I will determine whether
modulation of astrocytic membralin neuroinflammatory pathways can alter pathogenic effects in an AD mouse
model (Aim 2). In the R00 phase of this study, I will investigate modulation of a membralin-dependent astrocytic
TREM2-dependent DAM switch in microglia (Aim 3). The proposed study characterizing the gliosis induction
mechanisms in AD, will provide insight into neuroprotective membralin-associated astrocyte pathways that can
limit glutamatergic excitotoxicity and neuroinflammation through cell-autonomous and non-cell autonomous
...

## Key facts

- **NIH application ID:** 10593823
- **Project number:** 3K99AG066960-02S1
- **Recipient organization:** SANFORD BURNHAM PREBYS MEDICAL DISCOVERY INSTITUTE
- **Principal Investigator:** Lu-Lin Jiang
- **Activity code:** K99 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $131,298
- **Award type:** 3
- **Project period:** 2020-07-01 → 2022-09-29

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10593823

## Citation

> US National Institutes of Health, RePORTER application 10593823, A Role of Astrocyte and Microglia Interplay in Alzheimer's Disease (3K99AG066960-02S1). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10593823. Licensed CC0.

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