Berislav V. Zlokovic, United States of America

University of Southern California Zilkha Neurogenetic Institute
Berislav Zlokovic, MD, PhD is the director of the Zilkha Neurogenetic Institute, Professor and Chair of the Department of Physiology & Neuroscience at the Keck School of Medicine, and Professor of Biology at Dornsife College of Letters, Arts and Sciences. Zlokovic studies the role of brain microcirculation, particularly the blood-brain barrier (BBB) in health and disease in the adult brain and during aging. Using animal models and studying human brain he has pioneered the neurovascular concept of Alzheimer’s disease, and showed that BBB breakdown can accumulate before neuronal and synaptic loss, and is an early biomarker of human cognitive dysfunction. He demonstrated that disrupted cross-talk between BBB-associated pericytes and brain capillary endothelial cells, and astrocytes and pericytes, within the neurovascular unit leads to neuronal dysfunction and loss, and that targeting these BBB pathways can reverse neurodegenerative process. He has identified genes and receptors at the BBB regulating levels of Alzheimer’s amyloid-beta toxin in the brain, which accumulates with aging and dementia. He has developed new techniques for studying neurovascular functions in animal models and the living human brain that have opened up new areas of research previously untouched. His findings contributed to Phase 2/3 trials for Alzheimer’s disease based on clearance, and stroke based on activated protein C pathway in the brain. Thomson Reuters and Clarivate Analytics listed Zlokovic as one of “The World’s Most Influential Scientific Minds” for ranking in top one percent of the most-cited authors in the field of neurosciences and behavioral sciences for 18 consecutive years (2002-2020). He received the MetLife Award for Medical Research, the Potamkin Prize from the American Academy of Neurology, the MERIT Award from NIA, the Javits Award from NINDS, and recently the 2019 USC Associates Award for Creativity in Research and Scholarship, “the highest honor the university faculty bestows on its members for distinguished intellectual achievements”. Zlokovic is a member of the AAAS and the European Academy of Sciences. He co-founded ZZ Biotech, a biotechnology company dedicated to developing new treatments for stroke and other CNS disorders.

Presenter of 5 Presentations

BLOOD-BRAIN BARRIER DYSFUNCTION AND COGNITIVE DECLINE IN APOE4 CARRIERS

Session Type
SYMPOSIUM
Date
10.03.2021, Wednesday
Session Time
12:00 - 14:00
Room
On Demand Symposia B
Lecture Time
12:30 - 12:45
Session Icon
On-Demand

Abstract

Abstract Body

OBJECTIVES: Vascular dysfunction contributes to dementia and Alzheimer’s disease (AD).

METHODS: We used an MRI technique to study blood-brain barrier (BBB) integrity in the living human brain, and biomarkers of the BBB injury in the CSF in APOE4 carriers and APOE3 homozygotes during preclinical stage and during early cognitive decline.

RESULTS: Individuals bearing APOE4 (e3/e4; e4/e4), the main susceptibility gene for AD, were distinguished from those without APOE4 (e3/e3 homozygotes) by breakdown in the BBB in the hippocampus and medial temporal lobe, regions responsible for memory encoding and other cognitive functions. This was apparent in cognitively unimpaired APOE4 carriers, and more severe in those with cognitive impairment, but was not related to Ab or tau pathology measured in the CSF or by PET. High baseline CSF levels of sPDGFRb, a biomarker of pericyte injury, predicted cognitive decline in APOE4 carriers even after controlling for Ab and tau status. Pericyte injury correlated with activation of the proinflammatory cyclophilin A-matrix metalloproteinase-9 pathway in the CSF causing BBB breakdown, which in turn induces neuronal stress related to leaked blood-derived neurotoxic proteins.

CONCLUSIONS: Breakdown in the BBB contributes to APOE4-mediated cognitive decline independently of AD pathology and might be a therapeutic target in APOE4 carriers.
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BLOOD-BRAIN BARRIER CELLULAR AND MOLECULAR MECHANISMS UNDERLYING NEURODEGENERATION, COGNITIVE DYSFUNCTION AND AD

Session Type
PRE CONFERENCE SYMPOSIUM
Date
09.03.2021, Tuesday
Session Time
10:00 - 14:50
Room
Pre-Conference 1
Lecture Time
14:10 - 14:30
Session Icon
On-Demand and Live Q&A

LIVE DISCUSSION & Q&A: WHY ARE THE VASCULAR COMPONENTS AND BLOOD-BRAIN/BLOOD-RETINA BARRIERS OF THE BRAIN AND EYE IMPORTANT CONTRIBUTORS TO THE TIPPING POINT BETWEEN HEALTH AND DISEASE?