Understanding the Vascular Link Between Traumatic Brain Injury and Alzheimer's Disease

Zhen Zhao, PhD
University of Southern California (Los Angeles, CA)
Year Awarded:
2019
Grant Duration:
July 1, 2019 to June 30, 2022
Disease:
Alzheimer's Disease
Award Amount:
$300,000
Grant Reference ID:
A2019218S
Award Type:
Standard
Award Region:
US Southwestern

This grant is made possible in part by support from Alzheimer’s Los Angeles

Zhen Zhao, PhD

Understanding the Cerebrovascular Link Between Traumatic Brain Injury and Alzheimer’s Disease

Summary

Traumatic brain injury (TBI) is a leading cause of injury deaths and disabilities in the United States and the most robust environmental risk factor for Alzheimer’s disease. Vascular impairment is also a hallmark of the pathological events after TBI, including local edema, blood-flow reduction and breakdown of blood-brain barrier, which may significantly increase Alzheimer’s risk. Therefore, it is plausible to draw a cerebrovascular link between TBI and Alzheimer’s disease. Here we propose to address the paucity of research in the cerebrovascular connection between TBI and Alzheimer’s disease, and investigate the cerebrovascular impairment induced by TBI and its impact on the susceptibility to Alzheimer’s disease in animal models.

Details

The goal of this project is to investigate the cerebrovascular link between traumatic brain injury (TBI) and Alzheimer’s disease, and mechanistically understand the vascular contribution to elevated risks for Alzheimer’s disease in preclinical models of TBI.

Our central hypothesis is that vascular dysfunctions after TBI tip the balance between the production and clearance of Alzheimer’s β-amyloid in brain, and directly contribute to Alzheimer’s pathogenesis and cognitive impairment. We propose to use rodent models of TBI, and determine: i) the cellular and molecular mechanisms by which TBI induces vascular dysfunctions and blood-brain barrier breakdown, and ii) how such vascular dysfunctions impair the clearance of β-amyloid through the cerebrovascular system, and accelerate amyloid pathologies and neurodegeneration.

By understanding the vascular impairment as a direct consequence of TBI, and its negative impact on the amyloid metabolism in the brain, as well as long-term cognitive changes in animals, we hope to build a research resource to bridge the knowledge gap between TBI and Alzheimer’s disease. The outcomes of the proposed studies will provide new insights into the true trigger of Alzheimer’s cascade by TBI, and identify a novel target based on blood-brain barrier and vascular dysfunctions for prognosis detection and potentially intervention of Alzheimer’s pathogenesis in TBI survivors in the future.

About the Researcher

Zhen Zhao received his Ph.D. from the Neuroscience Graduate Program at USC in 2009, where he investigated axonal branching as a fundamental step in establishing neuronal connectivity and plasticity during early neurodevelopment and identified extracellular natriuretic peptide hormones that precisely control sensory neuron branching patterns in the spinal cord. He later worked with Dr Berislav Zlokovic for a better understanding the vascular contributions to neurodegenerative diseases. As part of Zlokovic’s team, he defined the role of PICALM in brain clearance of Alzheimer’s amyloid peptides, as well as the role of brain pericytes in the pathogenesis of Alzheimer’s disease and cerebral small vessel disease. He established his own research lab at USC in 2017, and his team is keen to understand the functions of Alzheimer’s risk genes in our central nervous system. His research objective is to explore the genetic, molecular and cellular mechanisms of neurodegeneration in Alzheimer’s disease, understand the crosstalk between the components of the neurovascular unit in health and during pathogenesis, and discover new approaches to restore the neurovascular and neuroimmune functions for the treatment of Alzheimer’s and other neurodegenerative diseases.

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