MITOCHONDRIAL CALCIUM UPTAKE IN ALZHEIMER?S DISEASE - ABSTRACT: ALZHEIMER'S DISEASE (AD) IS CHARACTERIZED B…

Assistance award details

Assistance award identifier

ASST_NON_R00AG065445_075

FAIN

R00AG065445

Recipient

WAKE FOREST UNIVERSITY HEALTH SCIENCES

Awarding agency

Department of Health and Human Services

Funding agency

Department of Health and Human Services

Assistance listing (CFDA)

93.866

Total obligated

$922,097

Period

Aug 15, 2020 – Aug 31, 2025

Fiscal year

2022

Place of performance state

NC

Source file

FY2022_All_Assistance_Full_20261006.zip

Description

MITOCHONDRIAL CALCIUM UPTAKE IN ALZHEIMER?S DISEASE - ABSTRACT: ALZHEIMER'S DISEASE (AD) IS CHARACTERIZED BY THE LOSS OF MEMORY ACCOMPANIED BY NEURONAL CELL DEATH AND METABOLIC DYSFUNCTION. NUMEROUS STUDIES HAVE REPORTED A DYSREGULATION IN NEURONAL INTRACELLULAR CALCIUM (1CA2+) SIGNALING AS AN EARLY EVENT IN AD PATHOGENESIS. IT IS THOUGHT THAT A PROLONGED ELEVATION IN NEURONAL 1CA2+ PROMOTES EXCESSIVE MITOCHONDRIAL CALCIUM (MCA2+) UPTAKE, YET TO DATE NO STUDY HAS EXAMINED THE CONTRIBUTION OF MCA2+ UPTAKE TO DISEASE PROGRESSION. SINCE MCA2+ FLUX IS AN IMPORTANT REGULATOR OF CELLULAR RESPIRATION AND CELL DEATH, BOTH OF WHICH ARE INVOLVED IN AD PATHOGENESIS, WE HYPOTHESIZE THAT MCA2+ OVERLOAD IS A KEY CONTRIBUTOR TO AD PATHOLOGY AND MAY CONTRIBUTE TO METABOLIC DEFICITS AND NEURONAL DEMISE. TO DEFINE THE ROLE OF MCA2+ EXCHANGE IN AD WE HAVE GENERATED 3XTG-AD MUTANT MICE WITH NEURONAL-SPECIFIC DELETION OF MITOCHONDRIAL CALCIUM UNIPORTER (MCU), WHICH IS REQUIRED FOR MCA2+ UPTAKE. IN ADDITION, WE HAVE GENERATED A GAIN-OF-FUNCTION MUTANT MOUSE EXPRESSING THE RECENTLY IDENTIFIED MITOCHONDRIAL CALCIUM UNIPORTER BETA SUBUNIT (MCUB). MCUB WAS RECENTLY REPORTED AS A NEGATIVE REGULATOR OF MCA2+ UPTAKE AND WE HAVE OBSERVED SUBSTANTIAL CHANGES IN ITS EXPRESSION IN AD. THESE MODELS WILL ALLOW CAUSATIVE EXPERIMENTATION TO TEST IF MCA2+ UPTAKE DRIVES AD PROGRESSION. MICE WILL BE EXAMINED FOR ALTERATIONS IN MEMORY, AMYLOIDOSIS, TAU-PATHOLOGY, OXIDATIVE STRESS, SYNAPTIC AND METABOLIC FUNCTION. PRELIMINARY DATA SUGGEST THAT MCA2+ UPTAKE OVERLOAD IMPAIRS THE CLEARANCE OF MISFOLDED PROTEINS AND DYSFUNCTIONAL MITOCHONDRIA. THEREFORE, WE WILL MECHANISTICALLY EXAMINE THE LINK BETWEEN MCA2+ EXCHANGE AND AUTOPHAGIC AND MITOPHAGIC PATHWAYS. OPTIMALLY, THE PROPOSED STUDIES WILL DISCOVER NEW THERAPEUTIC TARGETS FOR AD AND ASSOCIATED MITOCHONDRIAL DYSFUNCTION AND PROVIDE A TRAINING AND RESEARCH PLATFORM TO PROMOTE THE PIS INDEPENDENT RESEARCH CAREER.