CEREBROVASCULAR MITOCHONDRIA AS MEDIATORS OF NEUROINFLAMMATION IN ALZHEIMER'S DISEASE - ABSTRACT IN ALZHEIM…

Assistance award details

Assistance award identifier

ASST_NON_R00AG083227_075

FAIN

R00AG083227

Recipient

UNIVERSITY OF PUERTO RICO MEDICAL SCIENCES CAMPUS

Awarding agency

Department of Health and Human Services

Funding agency

Department of Health and Human Services

Assistance listing (CFDA)

93.866

Total obligated

$248,999

Period

Aug 1, 2023 – Jan 31, 2029

Fiscal year

2026

Place of performance state

PR

Source file

FY2026_All_Assistance_Full_20261006.zip

Description

CEREBROVASCULAR MITOCHONDRIA AS MEDIATORS OF NEUROINFLAMMATION IN ALZHEIMER'S DISEASE - ABSTRACT IN ALZHEIMER’S DISEASE (AD), AND TO A LESSER EXTENT IN NON-DEMENTED INDIVIDUALS, DEPOSITION OF AMYLOID Β (AΒ) IS FOUND AROUND CEREBRAL VESSELS, A CONDITION CALLED CEREBRAL AMYLOID ANGIOPATHY (CAA). IT IS LIKELY THAT THE DEVELOPMENT OF CAA, AND CONSEQUENTLY NEUROVASCULAR UNIT (NVU) DYSFUNCTION, IN AD MAY RESULT FROM FAILURE OF AΒ CLEARANCE PATHWAYS. IMPORTANTLY, ALL AΒ CLEARANCE PATHWAYS INVOLVE MOVEMENT OF AΒ TOWARDS THE VASCULATURE FOR ELIMINATION. CEREBROVASCULAR ENDOTHELIAL CELLS (EC), WHICH LINE ALL BRAIN VESSELS, ARE THE GATEKEEPERS OF THE BRAIN AND ARE RESPONSIBLE FOR THE MAINTENANCE OF CEREBRAL HOMEOSTASIS THROUGH THE BLOOD-BRAIN BARRIER (BBB). THE DEVELOPMENT OF CAA SEVERELY IMPACTS BRAIN HEALTH SINCE IT RESULTS IN EC DEATH, BBB BREAKDOWN, MICROHEMORRHAGES, PARENCHYMAL AΒ ACCUMULATION, AND IS ONE OF THE EARLIEST TRIGGERS FOR AD PROGRESSION. EC DYSFUNCTION ALSO AFFECTS OTHER CELLS OF THE NVU, SUCH AS ASTROCYTES OR MICROGLIA, THROUGH FINELY REGULATED COMMUNICATION MECHANISM BETWEEN THESE CELLS. THEREFORE, CAA-MEDIATED EC DYSFUNCTION MAY ALSO PRECIPITATE NEUROINFLAMMATION IN AD. OUR PRELIMINARY DATA SUGGESTS THAT EC MITOCHONDRIA SERVE AS IMPORTANT SENSORS OF AΒ DAMAGE. PREVIOUS STUDIES HAVE SHOWN THAT MITOCHONDRIA ARE RESPONSIBLE FOR THE ACTIVATION OF INFLAMMATORY PATHWAYS THROUGH THE RELEASE OF MITOCHONDRIAL DANGER ASSOCIATED MOLECULAR PATTERNS (MTDAMPS), INCLUDING MITOCHONDRIAL REACTIVE OXYGEN SPECIES (MTROS), DUE TO FORMATION OF THE PATHOLOGICAL MITOCHONDRIAL PERMEABILITY TRANSITION PORE (MPTP). BOTH CEREBROVASCULAR DYSFUNCTION AND INFLAMMATION ARE SHOWN EARLY IN DISEASE PATHOGENESIS, SUGGESTING THAT EARLY EC (AND THUS, BBB) DYSFUNCTION MAY DRIVE AND PERPETUATE AD PATHOLOGY ALSO BY TRIGGERING WIDESPREAD NEUROINFLAMMATION. HERE, WE WILL TEST THE HYPOTHESIS THAT AΒ INDUCES MITOCHONDRIAL DYSFUNCTION IN CEREBRAL ECS THROUGH DELETERIOUS ALTERATIONS IN MITOCH