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

> **NIH NIH K99** · SANFORD BURNHAM PREBYS MEDICAL DISCOVERY INSTITUTE · 2020 · $129,870

## Abstract

PROJECT SUMMARY
Alzheimer's disease (AD) is the most common neurodegenerative disease affecting over 3 million Americans
yearly, and features the extracellular accumulation of β-amyloid, intracellular tau aggregates, and aberrant glial
pathology. Glial dysfunction can trigger excitotoxicity and neuroinflammation, which is invariably linked to AD
pathogenesis. Reactive astrocyte and microglia triggers in AD pathogenesis are not yet clear.
Previously, I identified a novel ER component, membralin (TMEM259), as an important disease modifier in the
pathogenesis of AD and Amyotrophic Lateral Sclerosis (ALS). Membralin can modulate the integrity and activity
of the γ-secretase complex, and downregulating membralin expression in a mouse model of AD (TgCRND8) can
exacerbate 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-specific membralin deletion can
manifest severe neuroinflammatory pathological consequences, as demonstrated by robust elevation of gliotic
markers including GFAP (astrocytes), IBA1 and CD68 (microglia). Transcriptomic analysis of astrocyte
conditional knockout animals confirms the upregulation of genes associated with gliosis, neuroinflammation and
abnormal immune response. Membralin levels are reduced in both AD brain and ALS spinal cord. Excitotoxicity,
EAAT2 dysfunction and gliosis are common pathological features in AD and ALS. Moreover, a recent genome-
wide association (GWAS) study demonstrated 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 molecular triggering mechanisms in 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 mechanisms. In completing the ...

## Key facts

- **NIH application ID:** 9953862
- **Project number:** 1K99AG066960-01
- **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:** 2020
- **Award amount:** $129,870
- **Award type:** 1
- **Project period:** 2020-07-01 → 2022-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9953862

## Citation

> US National Institutes of Health, RePORTER application 9953862, A Role of Astrocyte and Microglia Interplay in Alzheimer's Disease (1K99AG066960-01). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9953862. Licensed CC0.

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