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

Role of Astrocyte EAAT2/GLT1 Failure in Alzheimer's Disease Pathogenesis

Award Number: R01AG075338
ORGANIZATION: NATIONAL INSTITUTE ON AGING
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 04/01/2022
PERIOD OF PERFORMANCE END DATE: 09/30/2025

Group Awards By:

View Award Description

Role of Astrocyte EAAT2/GLT1 Failure in Alzheimer's Disease Pathogenesis - Astrocytes are ideally positioned to support neuronal/synaptic needs for trophic factors, metabolic homeostasis, and protection from toxicity. While reactive astrogliosis is a prominent feature of AD, this offers very limited insight about how astrocytes influence the disease process or how they may be harmed. One of the most important functions of astrocytes is to clear extracellular glutamate to prevent excitotoxicity. Glutamate taken up by astrocytes is also used as a metabolic substrate for biosynthesis of other neuro- transmitters like GABA. Thus, there are at least two major ways astrocytic glutamate clearance protects the brain. In cortex and hippocampus, the glutamate transporter Slc1a2 (also called GLT1 or EAAT2) plays the most important role in glutamate clearance. Most, but not all Slc1a2 is in astrocytes. Our research team has shown that: (i) Slc1a2 is disturbed in AD; (ii) Slc1a2 loss in an AD mouse model accelerates onset of cognitive impairment; (iii) A42 slows synaptically-released glutamate uptake in hippo- campal slices; and (iv) mice with reduced astrocytic Slc1a2 display significant transcriptomic overlaps with AD. These data complement strong work from other groups and collectively argue that Slc1a2 dysfunction may play an important role in AD. However, additional critical questions need to be answered to better understand how astrocytic Slc1a2 may interact with A42 and tau pathology. Specifically, is there pathogenic synergy among these processes? In AD more needs to be uncovered about the relationship between neurons and the fine (often GFAP-negative) astrocytic processes expressing nearly all Slc1a2 in the brain—an anatomical relationship that is crucial to their function. In addition, there is insufficient data supporting the hypothesis that astrocytic Slc1a2 can play a contributing or causal role in exacerbating A42 and tau pathology. The goal of this project is to fill these knowledge gaps. First, we will use novel mice with reduced Slc1a2 specifically in astrocytes; and with adenoviral vectors (AAVs) expressing A42 and tauP301L, dissect the in vivo molecular interactions between these pathogenic pathways. We will address whether astrocytes are lost in response to A42 and/or tau. We will use a novel lentivirus system expressing Slc1a2, which infects astrocytes, to test whether specifically rescuing astrocytic Slc1a2 ameliorates neuropathology, as well as Slc1a2 function. Second, using state-of-the art patch clamp methods that directly measure astrocyte glutamate clearance, dissect how Slc1a2 loss, A42, and tau expression interact to affect astrocytic glutamate clearance. We will address how these pathogenic processes influence astrocytic Slc1a2 that regulate synaptic network excitability by supporting GABAergic transmission. Third, using well-characterized postmortem brains from control, prodromal, and AD patients we will test the potential translational significance of the glutamate transporter and astrocyte neuropathology we have reported and is suggested by our new preliminary data. Together, these data hold promise of advancing our knowledge of Slc1a2 as a potential molecular target for intervention 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: 2026 ( Subtotal = $833,758 )
2026	2026	RESEARCH FOUNDATION FOR THE STATE UNIVERSITY OF NEW YORK, THE	1400 WASHINGTON AVE	ALBANY	NY	12222	ALBANY	USA	Aging Research	003	5	3/17/2026	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$0
2026	2026	RESEARCH FOUNDATION FOR THE STATE UNIVERSITY OF NEW YORK, THE	1400 WASHINGTON AVE	ALBANY	NY	12222	ALBANY	USA	Aging Research	002	5	3/2/2026	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$78,072
2026	2026	RESEARCH FOUNDATION FOR THE STATE UNIVERSITY OF NEW YORK, THE	1400 WASHINGTON AVE	ALBANY	NY	12222	ALBANY	USA	Aging Research	001	5	2/18/2026	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$755,686
2026	2025	SEATTLE INSTITUTE FOR BIOMEDICAL AND CLINICAL RESEARCH	1660 S COLUMBIAN WAY	SEATTLE	WA	98108	KING	USA	Aging Research	004	4	3/25/2026	NON-COMPETING CONTINUATION	$0
2026	2025	SEATTLE INSTITUTE FOR BIOMEDICAL AND CLINICAL RESEARCH	1660 S COLUMBIAN WAY	SEATTLE	WA	98108	KING	USA	Aging Research	000	4	2/18/2026	NON-COMPETING CONTINUATION	$0
														Subtotal = $833,758

Issue Date FY: 2025 ( Subtotal = $701,077 )
2025	2025	SEATTLE INSTITUTE FOR BIOMEDICAL AND CLINICAL RESEARCH	1660 S COLUMBIAN WAY	SEATTLE	WA	98108	KING	USA	Aging Research	001	4	8/11/2025	NON-COMPETING CONTINUATION	$57,231
2025	2025	SEATTLE INSTITUTE FOR BIOMEDICAL AND CLINICAL RESEARCH	1660 S COLUMBIAN WAY	SEATTLE	WA	98108	KING	USA	Aging Research	000	4	1/15/2025	NON-COMPETING CONTINUATION	$643,846
														Subtotal = $701,077

Issue Date FY: 2024 ( Subtotal = $719,265 )
2024	2024	SEATTLE INSTITUTE FOR BIOMEDICAL AND CLINICAL RESEARCH	1660 S COLUMBIAN WAY	SEATTLE	WA	98108	KING	USA	Aging Research	001	3	5/17/2024	NON-COMPETING CONTINUATION	$71,926
2024	2024	SEATTLE INSTITUTE FOR BIOMEDICAL AND CLINICAL RESEARCH	1660 S COLUMBIAN WAY	SEATTLE	WA	98108	KING	USA	Aging Research	000	3	1/18/2024	NON-COMPETING CONTINUATION	$647,339
														Subtotal = $719,265

Issue Date FY: 2023 ( Subtotal = $726,367 )
2023	2023	SEATTLE INSTITUTE FOR BIOMEDICAL AND CLINICAL RESEARCH	1660 S COLUMBIAN WAY # 151F	SEATTLE	WA	98108	KING	USA	Aging Research	000	2	1/18/2023	NON-COMPETING CONTINUATION	$726,367
														Subtotal = $726,367

Issue Date FY: 2022 ( Subtotal = $798,159 )
2022	2022	SEATTLE INSTITUTE FOR BIOMEDICAL AND CLINICAL RESEARCH	1660 S COLUMBIAN WAY # 151F	SEATTLE	WA	98108	KING	USA	Aging Research	000	1	3/17/2022	NEW	$796,461
2022	2022	SEATTLE INSTITUTE FOR BIOMEDICAL AND CLINICAL RESEARCH	1660 S COLUMBIAN WAY # 151F	SEATTLE	WA	98108	KING	USA	Aging Research	001	1	4/12/2022	NEW	$1,698
														Subtotal = $798,159

Grand Total All Awards = $3,778,626

Top

All Categories

About

Search

Reports

Data Submission

Award Information

Role of Astrocyte EAAT2/GLT1 Failure in Alzheimer's Disease Pathogenesis

Award Number: R01AG075338

ORGANIZATION: NATIONAL INSTITUTE ON AGING

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

PERIOD OF PERFORMANCE START DATE: 04/01/2022

PERIOD OF PERFORMANCE END DATE: 09/30/2025

Federal Websites

Department of Health & Human Services

HHS Operating Divisions

HHS Staff Divisions

Download A Document Viewer