ASSESSING THE FUNCTIONAL CONSEQUENCES OF TAU-RELATED VASCULATURE CHANGES USING IN VIVO IMAGING - PROJECT SU…

Assistance award details

Assistance award identifier

ASST_NON_R00AG061259_075

FAIN

R00AG061259

Recipient

THE GENERAL HOSPITAL CORPORATION

Awarding agency

Department of Health and Human Services

Funding agency

Department of Health and Human Services

Assistance listing (CFDA)

93.866

Total obligated

$779,632

Period

Jul 15, 2021 – Jun 30, 2024

Fiscal year

2021

Place of performance state

MA

Source file

FY2021_All_Assistance_Full_20261006.zip

Description

ASSESSING THE FUNCTIONAL CONSEQUENCES OF TAU-RELATED VASCULATURE CHANGES USING IN VIVO IMAGING - PROJECT SUMMARY/ABSTRACT VASCULAR CHANGES ARE INCREASINGLY COMMON WITH AGE AND A RISK FACTOR FOR SOME FORMS OF COGNITIVE IMPAIRMENT INCLUDING ALZHEIMER'S DISEASE (AD). IN PARTICULAR, ALTERATIONS TO CEREBRAL PERFUSION HAVE BEEN WIDELY REPORTED, WITH DECREASED BLOOD FLOW OBSERVED IN CORTICAL AND LIMBIC REGIONS ASSOCIATED WITH THE ACCUMULATION OF AMYLOID BETA PLAQUES AND TAU-CONTAINING NEUROFIBRILLARY TANGLES. THOUGH NOT EXPRESSED BY CELLS THAT MAKE UP CEREBRAL VASCULATURE, THE NEURONAL PROTEIN TAU HAS BEEN OBSERVED INSIDE OF THE VASCULAR ENDOTHELIUM IN POST MORTEM TISSUE SECTIONS HIGHLIGHTING THE INTRIGUING POSSIBILITY THAT IT MAY DIRECTLY AFFECT ENDOTHELIAL CELLS. IN MICE, OVEREXPRESSION OF TAU APPEARS TO ALTER VASCULAR DENSITY, REDUCE AVERAGE VESSEL DIAMETER PARTICULARLY WITHIN THE CAPILLARY BED, AND INCREASE THE INCIDENCE OF VESSELS BLOCKED BY LEUKOCYTES. THESE FINDINGS COULD EXPLAIN, IN PART, ALTERED CEREBRAL PERFUSION CHANGES IN ALZHEIMER'S DISEASE PATIENTS, WHICH MAY BE A KEY CONTRIBUTOR TO COGNITIVE DECLINE. THE OVERALL GOAL OF THIS PROJECT IS TO DETERMINE HOW THESE TAU-INDUCED VASCULAR ALTERATIONS OBSERVED IN MICE AFFECT CEREBRAL PERFUSION AND, ULTIMATELY, NEURODEGENERATION. EXPERIMENTS WILL BE CARRIED OUT IN AGING TAU OVEREXPRESSING MICE CARRYING THE HUMAN P301L MUTATION (TG4510 LINE) AND ADVANCED IN VIVO IMAGING METHODS. TO ASSESS CEREBRAL PERFUSION, KEY MEASUREMENTS WILL BE MADE IN AWAKE MICE BY TWO-PHOTON MICROSCOPY INCLUDING RED BLOOD CELL FLOW, CEREBRAL OXYGENATION, AND OF THE HEMODYNAMIC RESPONSE USING A VISUAL STIMULATION PARADIGM. IF TAU INDUCES EARLY VASCULAR DYSFUNCTION, IT WILL BE EVIDENT BY A REDUCTION IN HEMODYNAMIC RESPONSE AND POOR TISSUE OXYGENATION, WHICH WILL LEAD TO SUBSEQUENT NEURON LOSS. FURTHER, REDUCED PERFUSION COULD BE PARTIALLY EXPLAINED BY THE OBSERVATION OF VESSELS BLOCK BY LEUKOCYTES. IN A SECOND SET OF EXPERIMENTS, A NOVEL CRANIAL WIN