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.

National Institute of Health (NIH)
National Institute on Aging (NIA)
Research Project (R01)
Project #
Application #
Study Section
Brain Injury and Neurovascular Pathologies Study Section (BINP)
Program Officer
Petanceska, Suzana
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
University of Southern California
Schools of Medicine
Los Angeles
United States
Zip Code
Shi, Yingxiao; Lin, Shaoyu; Staats, Kim A et al. (2018) Haploinsufficiency leads to neurodegeneration in C9ORF72 ALS/FTD human induced motor neurons. Nat Med 24:313-325
Sweeney, Melanie D; Kisler, Kassandra; Montagne, Axel et al. (2018) The role of brain vasculature in neurodegenerative disorders. Nat Neurosci 21:1318-1331
Montagne, Axel; Nikolakopoulou, Angeliki M; Zhao, Zhen et al. (2018) Pericyte degeneration causes white matter dysfunction in the mouse central nervous system. Nat Med 24:326-337
Sweeney, Melanie D; Zlokovic, Berislav V (2018) A lymphatic waste-disposal system implicated in Alzheimer's disease. Nature 560:172-174
Sweeney, Melanie D; Sagare, Abhay P; Zlokovic, Berislav V (2018) Blood-brain barrier breakdown in Alzheimer disease and other neurodegenerative disorders. Nat Rev Neurol 14:133-150
Kisler, Kassandra; Nelson, Amy R; Montagne, Axel et al. (2017) Cerebral blood flow regulation and neurovascular dysfunction in Alzheimer disease. Nat Rev Neurosci 18:419-434
Montagne, Axel; Zhao, Zhen; Zlokovic, Berislav V (2017) Alzheimer's disease: A matter of blood-brain barrier dysfunction? J Exp Med 214:3151-3169
Nelson, Amy R; Sagare, Abhay P; Zlokovic, Berislav V (2017) Role of clusterin in the brain vascular clearance of amyloid-?. Proc Natl Acad Sci U S A 114:8681-8682
Kisler, Kassandra; Nelson, Amy R; Rege, Sanket V et al. (2017) Pericyte degeneration leads to neurovascular uncoupling and limits oxygen supply to brain. Nat Neurosci 20:406-416
Nikolakopoulou, Angeliki Maria; Zhao, Zhen; Montagne, Axel et al. (2017) Regional early and progressive loss of brain pericytes but not vascular smooth muscle cells in adult mice with disrupted platelet-derived growth factor receptor-? signaling. PLoS One 12:e0176225

Showing the most recent 10 out of 39 publications