Inhibition of MMP-9 Activity Impairs Working Memory in Zebrafish Through Changes in Overall Hippocampal Excitation

Vanderbilt University Medical Center, Nashville TN

Investigators

Abstract

Alzheimer’s disease (AD) is the most common type of dementia and according to the Alzheimer’s Association, it currently affects approximately 7.2 million Americans age 65 and older. Even more striking, AD prevalence is expected to increase to nearly 13 million Americans by 2050. Unfortunately, despite this high prevalence, the molecular and cellular mechanisms underlying the onset of AD remains to be fully elucidated. Vascular risk factors, such as hypertension, are becoming increasingly recognized as key contributors to dementia. Hypertension affects nearly half the adult population in the United Stats, making it one of the most prevalent yet modifiable risk factors for AD and related dementias (ADRDs). Therefore, unraveling the molecular and cellular mechanisms by which hypertension leads to ADRDs will contribute to finding novel therapeutic targets with the potential to prevent and/or ameliorate cognitive deficits. Matrix Metalloproteinase-9 (MMP-9) is a molecular player associated with learning and memory and is dysregulated in both hypertension and dementia. Therefore, the purpose of my K00 project is to understand the molecular and cellular mechanisms that link hypertension to the onset of dementia through MMP-9 dysregulation in the vasculature. My research will focus on the role of MMP-9 activity in modulating cerebral blood flow (CBF), neuronal activity, and cognitive impairment in a mouse model of hypertension. Overall, the central hypothesis is that hypertension leads to increased MMP-9 activity, which will impair CBF regulation and neuronal activity in the retrosplenial cortex (RSC), contributing to impaired neuronal activity during demanding mnemonic tasks such as associative memory. In addition to providing me with a unique training opportunity, my three aims will utilize a repertoire of state-of-the-art techniques and translational data from participants, and its successful completion has the potential to highly impact the field of neurodegeneration by uncovering potential novel disease-modifying therapeutic targets to prevent and ameliorate cognitive deficits associated with hypertension.