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

Blood-Brain Barrier Dysfunction in Alzheimer’s Disease: New Mechanistic Insights and Therapeutic Strategies

Award Number: R01AG090534
ORGANIZATION: NATIONAL INSTITUTE ON AGING
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 05/01/2025
PERIOD OF PERFORMANCE END DATE: 01/31/2030

Group Awards By:

View Award Description

Blood-Brain Barrier Dysfunction in Alzheimer’s Disease: New Mechanistic Insights and Therapeutic Strategies - Amyloid β (Aβ) is a key driver of blood-brain barrier dysfunction in Alzheimer’s disease (AD). A leaky and dysfunctional barrier, in turn, contributes to AD pathology and cognitive decline. In addition to Aβ, another key driver of AD pathology is microtubule-associated protein tau (tau). In AD, intracellular tau accumulates in neurons, contributing to neurodegeneration and cognitive decline. Tau also exists as extracellular tau, which activates various signaling pathways. Importantly, elevated extracellular tau contributes to neurodegeneration and cognitive decline. We found that extracellular tau induces barrier dysfunction and is transported across the brain capillary endothelium into the vascular lumen. These findings support the conclusion that both Aβ and tau contribute to barrier dysfunction and cognitive decline in AD. However, the mechanism underlying tau-induced barrier dysfunction is unknown and tau transport has not been described. Thus, therapeutic strategies that repair Aβ/tau-induced barrier dysfunction are not available. In this application, we address this critical unmet need and propose to determine the mechanistic link between tau signaling and barrier dysfunction, define tau transport at the blood-brain barrier, and develop a strategy to repair Aβ/tau-induced barrier dysfunction. Our objective in this proposal is to establish a mechanism-based intervention targeting Aβ/tau to treat barrier dysfunction in AD. Based on preliminary data, our central hypothesis is that targeting SIRT1/NOX repairs Aβ/tau-mediated barrier dysfunction and slows cognitive decline in APP/tau models. Our rationale is that this proposed research has the potential to provide a basis for a disease-modifying intervention to treat barrier dysfunction in AD patients. The hypothesis will be tested by pursuing three specific aims: 1) Identify the mechanism responsible for tau-induced barrier dysfunction. 2) Determine tau transport across the blood-brain barrier. 3) Develop a therapeutic intervention to repair Ab/tau-induced barrier dysfunction. In Aim 1, we will identify signaling steps through which tau induces barrier dysfunction in isolated brain capillaries from wildtype and KO mice and in isolated human brain capillaries. In Aim 2, we will define tau transport across the capillary endothelium in vivo and in human brain capillaries. In Aim 3, we will block Ab and tau signaling to repair barrier dysfunction and evaluate the benefit of this strategy to slow cognitive decline in two preclinical APP/tau models. The proposed research is innovative because it represents a new and substantive departure from the status quo to a disease-modifying combination therapy focused on both Aβ and tau aimed at new molecular targets to repair barrier dysfunction and slow cognitive decline. The proposed research is significant because it is expected to create a paradigm shift in our understanding of barrier dysfunction in AD and constitute a crucial step toward developing a mechanism-based intervention to repair barrier dysfunction in patients.


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 = $713,257 )
2026	2026	UNIVERSITY OF KENTUCKY RESEARCH FOUNDATION, THE	500 S LIMESTONE	LEXINGTON	KY	40526	FAYETTE	USA	Aging Research	001	2	2/24/2026	NON-COMPETING CONTINUATION	$71,324
2026	2026	UNIVERSITY OF KENTUCKY RESEARCH FOUNDATION, THE	500 S LIMESTONE	LEXINGTON	KY	40526	FAYETTE	USA	Aging Research	000	2	1/27/2026	NON-COMPETING CONTINUATION	$641,933
														Subtotal = $713,257

Issue Date FY: 2025 ( Subtotal = $758,744 )
2025	2025	UNIVERSITY OF KENTUCKY RESEARCH FOUNDATION, THE	500 S LIMESTONE	LEXINGTON	KY	40526	FAYETTE	USA	Aging Research	000	1	4/21/2025	NEW	$758,744
														Subtotal = $758,744

Grand Total All Awards = $1,472,001

Top

All Categories

About

Search

Reports

Data Submission

Award Information

Blood-Brain Barrier Dysfunction in Alzheimer’s Disease: New Mechanistic Insights and Therapeutic Strategies

Award Number: R01AG090534

ORGANIZATION: NATIONAL INSTITUTE ON AGING

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 05/01/2025

PERIOD OF PERFORMANCE END DATE: 01/31/2030

Federal Websites

Department of Health & Human Services

HHS Operating Divisions

HHS Staff Divisions

Download A Document Viewer