Pericytes are essential cells of the neurovascular unit. They are embedded within the vascular membrane of brain capillaries making direct focal contacts with the endothelium. The existence and role of pericytes has been neglected for a long time. Interactions between endothelial cells and pericytes are important for normal functions of the capillary vessel wall. In the embryonic CNS, pericytes play a key role in the development of the microcirculation. Still, the field is at the beginning of a journey to fully understand and appreciate the biology of brain pericytes and its implications for neurological disorders. The major goals of the proposed research are to determine how pericyte deficiency in the adult and the aging brain affects key neurovascular functions and neuronal structure and function. Our central hypothesis is that pericytes maintain critical neurovascular functions which are essential for normal brain performance. We hypothesize that pericyte loss in the adult brain leads to a progressive age-dependent vascular damage by two parallel pathways: (1) reductions in brain microcirculation causing diminished capillary perfusion, reduced local CBF and hypoxic tissue damage;and (2) BBB disruption leading to brain accumulation of several neurotoxic and vasculotoxic macromolecules. We next hypothesize that pericyte loss from the adult brain leads to microvascular degeneration and vascular-mediated secondary neurodegenerative changes followed by a general inflammatory response. To test our hypothesis we propose to use 3 models of cerebrovascular hypoplasia mediated by (1) an inherited embryonic loss of CNS pericytes and PDGFR? global deficiency (i.e., F7 mutants), (2) an inducible pericyte loss in the adult CNS with intact signaling pathways in pericytes (i.e., NG2-Cre;Pdgfr?DTR mice) and (3) a primary cerebral endothelial hypoplasia in which pericytes remain intact (i.e., Meox2+/- mice) as a non-pericyte deficiency hypoplasia model with genetically intact PDGFR? signaling. Several state-of-the art techniques will be used including in vivo multiphoton microscopy, high resolution confocal microscopy, quantitative autoradiography, mathematical modeling of CBF and BBB permeability, methods to study neuronal structure and function (e.g., electrophysiology), behavioral tests and neuroinflammation. The proposed application will fill in the gap of our knowledge regarding the role of pericytes in the CNS and will likely have important implications for our understanding of a neurodegenerative process and treatment of it. We expect to generate definitive data showing that pericytes control key neurovascular functions necessary for normal structure and function of neurons and that loss of pericytes from the adult CNS has a key role in the development of microvascular and neuronal degeneration. This data should establish brain pericytes as a major new therapeutic target for neurodegenerative disorders.

Public Health Relevance

The annual health care costs for neurodegenerative disorders range in excess of a hundred billion dollars. Sadly, we do not have cure yet for any of these diseases. Understanding the role of pericytes in the adult and the aging brain will have profound implications for our understanding of neurological disorders and may ultimately guide the development of new therapeutic approaches for brain disorders.

Agency
National Institute of Health (NIH)
Type
Research Project (R01)
Project #
5R01AG039452-04
Application #
8705332
Study Section
Brain Injury and Neurovascular Pathologies Study Section (BINP)
Program Officer
Petanceska, Suzana
Project Start
Project End
Budget Start
Budget End
Support Year
4
Fiscal Year
2014
Total Cost
Indirect Cost
Name
University of Southern California
Department
Physiology
Type
Schools of Medicine
DUNS #
City
Los Angeles
State
CA
Country
United States
Zip Code
90089
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Montagne, Axel; Nation, Daniel A; Pa, Judy et al. (2016) Brain imaging of neurovascular dysfunction in Alzheimer's disease. Acta Neuropathol 131:687-707
Montagne, Axel; Toga, Arthur W; Zlokovic, Berislav V (2016) Blood-Brain Barrier Permeability and Gadolinium: Benefits and Potential Pitfalls in Research. JAMA Neurol 73:13-4
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Sagare, Abhay P; Sweeney, Melanie D; Makshanoff, Jacob et al. (2015) Shedding of soluble platelet-derived growth factor receptor-β from human brain pericytes. Neurosci Lett 607:97-101
Montagne, Axel; Pa, Judy; Zlokovic, Berislav V (2015) Vascular plasticity and cognition during normal aging and dementia. JAMA Neurol 72:495-6

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