MECHANISMS OF BLOOD-BRAIN BARRIER DETERIORATION IN VASCULAR COGNITIVE IMPAIRMENT AND ALZHEIMERS DISEASE - P…

Assistance award details

Assistance award identifier

ASST_NON_K00AG083111_075

FAIN

K00AG083111

Recipient

MASSACHUSETTS INSTITUTE OF TECHNOLOGY

Awarding agency

Department of Health and Human Services

Funding agency

Department of Health and Human Services

Assistance listing (CFDA)

93.866

Total obligated

$186,835

Period

Sep 11, 2023 – May 31, 2029

Fiscal year

2025

Place of performance state

MA

Source file

FY2025_All_Assistance_Full_20261006.zip

Description

MECHANISMS OF BLOOD-BRAIN BARRIER DETERIORATION IN VASCULAR COGNITIVE IMPAIRMENT AND ALZHEIMERS DISEASE - PROJECT SUMMARY/ABSTRACT WITH OUR EXPECTED LIFESPANS INCREASING, THE RAPIDLY EXPANDING AGING POPULATION IS BRINGING AN INCREASED PREVALENCE OF DEMENTIA, INCLUDING ALZHEIMER’S DISEASE (AD) AND VASCULAR COGNITIVE IMPAIRMENT (VCI). HOWEVER, THERE ARE STILL NO NEUROPROTECTIVE MEDICINES FOR TREATING PATIENTS WITH THESE CONDITIONS. AD AND VCI ARE THE MOST COMMON TYPES OF DEMENTIA AND IMPOSE A HUGE SOCIOECONOMIC BURDEN AS WELL AS DEVASTATING IMPACTS ON THE LIVES OF PATIENTS AND THEIR CAREGIVERS. BOTH OF THESE FORMS OF DEMENTIA ARE CHARACTERIZED BY DETERIORATION OF THE NEUROVASCULAR UNIT THAT FORMS THE BLOOD-BRAIN BARRIER (BBB), WHICH IN MANY CASES EVEN PRECEDES THE ONSET OF COGNITIVE DEFICITS. UNFORTUNATELY, HOWEVER, THE MECHANISMS OF BBB DETERIORATION IN AD AND VCI ARE UNCLEAR. AS A RESULT, THERE ARE NO THERAPIES TO PROTECT THE BBB. IN MY THESIS WORK, I HAVE ESTABLISHED THAT THE PROSTAGLANDIN DEGRADING ENZYME 15-HYDROXYPROSTAGLANDIN DEHYDROGENASE (15-PGDH) IS PATHOLOGICALLY ELEVATED IN BOTH HUMAN AD AND VCI IN HUMAN PATIENTS. I HAVE ALSO SHOWN THAT THE ENZYMATIC ACTIVITY OF 15-PGDH IN THE BRAIN IS INCREASED IN THE 5XFAD MOUSE MODEL OF AD, AS WELL AS NORMAL AGING. IMPORTANTLY, I HAVE ESTABLISHED THAT PHARMACOLOGIC AND GENETIC INHIBITION OF 15-PGDH IN 5XFAD MICE SHOWS ROBUST PROTECTION AGAINST BBB DETERIORATION AND OTHER AD-RELATED PATHOLOGY, INCLUDING COGNITIVE DEFICITS, IMPAIRED NEUROGENESIS, AND AXON DEGENERATION, INDEPENDENTLY OF AMYLOID Β PATHOLOGY. I HAVE ALSO FOUND THAT OF THE PROSTAGLANDINS, PROSTAGLANDIN D2 (PGD2) IS MOST PROMINENTLY ELEVATED IN THE BRAIN BY 15-PGDH INHIBITION IN 5XFAD MICE. THEREFORE, I HYPOTHESIZE THAT PGD2 IS RESPONSIBLE FOR 15-PGDH INHIBITION-MEDIATED PROTECTION OF THE BBB, AND THAT THIS IS RELATED TO IMPROVED ENDOTHELIAL CELL BARRIER FUNCTION. DURING THE F99 PORTION OF MY PROPOSAL, I WILL EVALUATE WHETHER 15-PGDH INHIBITION ALSO PROTECT