Official websites use .gov

A .gov website belongs to an official government organization in the United States.

Secure .gov websites use HTTPS

A lock ( 🔒 ) or https:// means you've safely connected to the .gov website. Share sensitive information only on official, secure websites.

Need Help

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

Award Number: K99AG066960
ORGANIZATION: NATIONAL INSTITUTE ON AGING
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: TRAINING/TRAINEESHIP
PERIOD OF PERFORMANCE START DATE: 07/01/2020
PERIOD OF PERFORMANCE END DATE: 09/29/2022

Group Awards By:

View Award Description

A Role of Astrocyte and Microglia Interplay in Alzheimer's Disease - 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 mechanisms. In completing the aims of this study, we may define new therapeutic targeting strategies through modulation of glial function in AD.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2023 ( Subtotal = -$105,493 )
2023	2022	SANFORD BURNHAM PREBYS MEDICAL DISCOVERY INSTITUTE	10901 N TORREY PINES RD	LA JOLLA	CA	92037	SAN DIEGO	USA	Aging Research	000	2	9/19/2023	SUPPLEMENT FOR EXPANSION	-$105,493
														Subtotal = -$105,493

Issue Date FY: 2022 ( Subtotal = $131,298 )
2022	2022	SANFORD BURNHAM PREBYS MEDICAL DISCOVERY INSTITUTE	10901 NORTH TORREY PINES RD	LA JOLLA	CA	92037	SAN DIEGO	USA	Aging Research	003	2	9/13/2022	SUPPLEMENT FOR EXPANSION	$0
2022	2022	SANFORD BURNHAM PREBYS MEDICAL DISCOVERY INSTITUTE	10901 NORTH TORREY PINES RD	LA JOLLA	CA	92037	SAN DIEGO	USA	Aging Research	001	2	7/14/2022	SUPPLEMENT FOR EXPANSION	$131,298
2022	2021	SANFORD BURNHAM PREBYS MEDICAL DISCOVERY INSTITUTE	10901 NORTH TORREY PINES RD	LA JOLLA	CA	92037	SAN DIEGO	USA	Aging Research	002	2	9/13/2022	NON-COMPETING CONTINUATION	$0
2022	2021	SANFORD BURNHAM PREBYS MEDICAL DISCOVERY INSTITUTE	10901 NORTH TORREY PINES RD	LA JOLLA	CA	92037	SAN DIEGO	USA	Aging Research	000	2	7/13/2022	NON-COMPETING CONTINUATION	$0
														Subtotal = $131,298

Issue Date FY: 2021 ( Subtotal = $129,870 )
2021	2021	SANFORD BURNHAM PREBYS MEDICAL DISCOVERY INSTITUTE	10901 NORTH TORREY PINES RD	LA JOLLA	CA	92037	SAN DIEGO	USA	Aging Research	000	2	6/30/2021	NON-COMPETING CONTINUATION	$129,870
														Subtotal = $129,870

Issue Date FY: 2020 ( Subtotal = $129,870 )
2020	2020	SANFORD BURNHAM PREBYS MEDICAL DISCOVERY INSTITUTE	10901 NORTH TORREY PINES RD	LA JOLLA	CA	92037	SAN DIEGO	USA	Aging Research	000	1	6/26/2020	NEW	$129,870
														Subtotal = $129,870

Grand Total All Awards = $285,545

Top

All Categories

About

Search

Reports

Data Submission

Award Information

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

Award Number: K99AG066960

ORGANIZATION: NATIONAL INSTITUTE ON AGING

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: TRAINING/TRAINEESHIP

PERIOD OF PERFORMANCE START DATE: 07/01/2020

PERIOD OF PERFORMANCE END DATE: 09/29/2022

Federal Websites

Department of Health & Human Services

HHS Operating Divisions

HHS Staff Divisions

Download A Document Viewer