Wednesday, October 15, 2025 10/15/2025

Stalled capillary flow: a novel mechanism for hypoperfusion in Alzheimer disease

Award Number: R01AG049952
ORGANIZATION: NATIONAL INSTITUTE ON AGING
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 05/15/2015
PERIOD OF PERFORMANCE END DATE: 04/30/2026

Group Awards By:

View Award Description

Stalled capillary flow: a novel mechanism for hypoperfusion in Alzheimer disease - Project Summary Cerebral blood flow (CBF) is reduced in Alzheimer’s disease (AD) patients and mouse models by ~20%, but there remains a limited understanding of the mechanisms causing this hypoperfusion or the potential therapeutic benefit of rescuing CBF deficits. Under the previous award, chronic in vivo two-photon excited fluorescence microscopy was used to study CBF in mouse models of AD. While no blood flow disruption in cortical arterioles or venules was observed, blood flow was found to be stalled in ~2% of cortical capillaries in mouse models of AD, as compared to ~0.4% in wild type controls. These capillary stalls appeared early in disease progression, were caused by arrested neutrophils, and had outsized impacts on CBF because they decreased flow speed in up- and down-stream vessels. Antibodies against the neutrophil surface protein Ly6G were serendipitously found to reduce the incidence of capillary stalls immediately, leading to a rescue of two-thirds of the CBF deficit, and, remarkably, to improved memory function within hours. Preliminary data further link this capillary stalling to cellular damage from reactive oxygen species (ROS). In this competitive renewal, the mechanisms underlying neutrophil arrest in capillaries in mouse models of AD and the consequences of improving CBF on AD-related pathology are explored. First, three different hypotheses about the mechanism of neutrophil arrest in capillary segments are tested: a focal constriction of the capillary by a pericyte that prevents neutrophil passage; binding of the neutrophil to increased inflammatory adhesion molecules on endothelial cells; or binding of the neutrophil to basement membrane and adhesion molecules exposed at widened gaps between endothelial cells. Second, the molecular and cellular origin of the ROS that leads to neutrophil arrest is determined using cell type-specific knockouts of ROS producing enzymes. Third, the impact of long-term CBF rescue on the deposition of amyloid- beta (Aβ), a driver of AD pathology, and on neuropathology will be quantified. Critical for this study are recently- developed knock-in mouse models of AD that may better capture the feedback of CBF reductions on expression of amyloid precursor protein (APP), which is cleaved to produce Aβ. Finally, cutting-edge three-photon excited fluorescence microscopy is used to enable imaging of the hippocampus to determine the role of capillary stalling in CBF deficits in one of the first regions of the brain that exhibits AD pathology. The hypothesis that brain hypoperfusion in AD is due to neutrophil arrest in capillaries is both novel and strongly supported by the findings under the previous award. The work proposed in this competitive renewal would uncover the mechanisms underlying that neutrophil arrest, which could suggest therapeutic targets to improve CBF that would be complementary to anti-amyloid and other treatment approaches for 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: 2025 ( Subtotal = $1,729,992 )
2025	2025	CORNELL UNIVERSITY	341 PINE TREE RD	ITHACA	NY	14850	TOMPKINS	USA	Aging Research	001	8	8/21/2025	NON-COMPETING CONTINUATION	$711,472
2025	2025	CORNELL UNIVERSITY	341 PINE TREE RD	ITHACA	NY	14850	TOMPKINS	USA	Aging Research	000	7	4/7/2025	EXTENSION WITH OR WITHOUT FUNDS	$711,472
2025	2024	CORNELL UNIVERSITY	341 PINE TREE RD	ITHACA	NY	14850	TOMPKINS	USA	Aging Research	000	7	4/7/2025	EXTENSION WITH OR WITHOUT FUNDS	$307,048
														Subtotal = $1,729,992

Issue Date FY: 2024 ( Subtotal = $826,304 )
2024	2024	CORNELL UNIVERSITY	341 PINE TREE RD	ITHACA	NY	14850	TOMPKINS	USA	Aging Research	000	7	5/13/2024	EXTENSION WITH OR WITHOUT FUNDS	$736,304
2024	2024	CORNELL UNIVERSITY	341 PINE TREE RD	ITHACA	NY	14850	TOMPKINS	USA	Aging Research	001	7	8/27/2024	SUPPLEMENT FOR EXPANSION	$90,000
														Subtotal = $826,304

Issue Date FY: 2021 ( Subtotal = $0 )
2021	2019	CORNELL UNIVERSITY	341 PINE TREE RD	ITHACA	NY	14850	TOMPKINS	USA	Aging Research	000	5	8/5/2021	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2019 ( Subtotal = $657,051 )
2019	2019	CORNELL UNIVERSITY, INC	373 PINE TREE RD	ITHACA	NY	14850	TOMPKINS	USA	Aging Research	000	5	7/22/2019	NON-COMPETING CONTINUATION	$327,322
2019	2019	CORNELL UNIVERSITY, INC	373 PINE TREE RD	ITHACA	NY	14850	TOMPKINS	USA	Aging Research	001	5	9/13/2019	SUPPLEMENT FOR EXPANSION	$329,729
														Subtotal = $657,051

Issue Date FY: 2018 ( Subtotal = $327,572 )
2018	2018	CORNELL UNIVERSITY, INC	373 PINE TREE RD	ITHACA	NY	14850	TOMPKINS	USA	Aging Research	000	4	8/6/2018	NON-COMPETING CONTINUATION	$327,572
														Subtotal = $327,572

Issue Date FY: 2017 ( Subtotal = $327,794 )
2017	2017	CORNELL UNIVERSITY, INC	373 PINE TREE RD	ITHACA	NY	14850	TOMPKINS	USA	Aging Research	000	3	5/19/2017	NON-COMPETING CONTINUATION	$295,013
2017	2017	CORNELL UNIVERSITY, INC	373 PINE TREE RD	ITHACA	NY	14850	TOMPKINS	USA	Aging Research	001	3	6/23/2017	NON-COMPETING CONTINUATION	$32,781
														Subtotal = $327,794

Issue Date FY: 2016 ( Subtotal = $327,993 )
2016	2016	CORNELL UNIVERSITY	373 PINE ROAD	ITHACA	NY	14850	TOMPKINS	USA	Aging Research	000	2	6/27/2016	NON-COMPETING CONTINUATION	$327,993
														Subtotal = $327,993

Issue Date FY: 2015 ( Subtotal = $328,169 )
2015	2015	CORNELL UNIVERSITY	373 PINE ROAD	ITHACA	NY	14850	TOMPKINS	USA	Aging Research	000	1	5/13/2015	NEW	$328,169
														Subtotal = $328,169

Grand Total All Awards = $4,524,875

Top

All Categories

About

Search

Reports

Data Submission

Award Information

Stalled capillary flow: a novel mechanism for hypoperfusion in Alzheimer disease

Award Number: R01AG049952

ORGANIZATION: NATIONAL INSTITUTE ON AGING

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 05/15/2015

PERIOD OF PERFORMANCE END DATE: 04/30/2026

Federal Websites

Department of Health & Human Services

HHS Operating Divisions

HHS Staff Divisions

Download A Document Viewer