Project Grant R21NS130331

PHARMACOLOGICAL INHIBITION OF NEP-LIKE ENZYMES IN TRAUMATIC BRAIN INJURY AND DEMENTIA - ABSTRACT RECENTLY, MY LABORATORY HAS FOUND THAT THE NEP-LIKE ENDOPEPTIDASES, NEPRILYSIN (NEP) AND NEP2, HAVE A ROLE IN ACUTE RECOVERY AFTER TRAUMATIC BRAIN INJURY (TBI). THIS HAS INTERESTING AND EXCITING IMPLICATIONS FOR THE TBI FIELD AS WELL AS FOR UNDERSTANDING RISK FACTORS FOR DEVELOPING DEMENTIA. THE CAUSAL LINKS BETWEEN TBI AND DEMENTIA ARE BECOMING BETTER UNDERSTOOD. MANY OF THE PATHOLOGICAL HALLMARKS OF ALZHEIMER'S DISEASE (AD) ARE SHARED WITH EARLY CHANGES IN TBI. OF NOTE ARE THE RAPID ELEVATIONS OF THE AMYLOID-BETA (AB) PEPTIDE AFTER TBI. NATURAL MECHANISMS OF CLEARANCE OF AB ARE IMPORTANT IN SLOWING THE PROGRESSION OF AD AND SO THESE CLEARANCE MECHANISMS MAY ALSO BE IMPORTANT IN TBI. BOTH NEP AND ITS HOMOLOG NEP2 DEGRADE AB AND ARE IMPORTANT FOR CONTROLLING CEREBRAL LEVELS OF THE PEPTIDE. WE PROPOSE A ROLE FOR THESE ENZYMES IN THE PROCESSES FOLLOWING TBI. TO FURTHER INVESTIGATE THE ROLE(S) OF NEP/NEP2 IN TBI WE WILL USE OUR APP HUMANIZED TRANSGENIC MICE AND ALTER THE ACTIVITY OF THESE ENZYMES IN A TBI CONTEXT IN BOTH SHORT (AIM 1) AND LONG-TERM (AIM 2) ASSESSMENTS. THIS PROJECT WILL DETERMINE THE IMPORTANCE OF NEP-LIKE ENZYMES IN THE ACUTE PATHOLOGY POST TBI AS WELL AS IN THE DEVELOPMENT DEMENTIA.