Pericytes control key neurovascular functions and neuronal phenotype in the adult brain and during brain aging.
Pericytes play a key role in the development of cerebral microcirculation. The exact role of pericytes in the neurovascular unit in the adult brain and during brain aging remains, however, elusive. Using adult viable pericyte-deficient mice, we show that pericyte loss leads to brain vascular damage by two parallel pathways: (1) reduction in brain microcirculation causing diminished brain capillary perfusion, cerebral blood flow, and cerebral blood flow responses to brain activation that ultimately mediates chronic perfusion stress and hypoxia, and (2) blood-brain barrier breakdown associated with brain accumulation of serum proteins and several vasculotoxic and/or neurotoxic macromolecules ultimately leading to secondary neuronal degenerative changes. We show that age-dependent vascular damage in pericyte-deficient mice precedes neuronal degenerative changes, learning and memory impairment, and the neuroinflammatory response. Thus, pericytes control key neurovascular functions that are necessary for proper neuronal structure and function, and pericyte loss results in a progressive age-dependent vascular-mediated neurodegeneration.
Department of Neurosurgery and Neurology, University of Rochester Medical Center, Center for Neurodegenerative and Vascular Brain Disorders, Rochester, NY 14642, USA.
Robert D
RD
Bell
Ethan A
EA
Winkler
Abhay P
AP
Sagare
Itender
I
Singh
Barb
B
LaRue
Rashid
R
Deane
Berislav V
BV
Zlokovic
D000375:Aging / Q000502:physiology*; D000818:Animals; D001345:Autoradiography; D001812:Blood-Brain Barrier / Q000502:physiology; D015153:Blotting, Western; D001921:Brain / Q000254:growth & development* / Q000502:physiology*; D002196:Capillaries / Q000502:physiology; D002560:Cerebrovascular Circulation / Q000502:physiology*; D004594:Electrophysiology; D005455:Fluorescent Antibody Technique; D007150:Immunohistochemistry; D020287:In Situ Nick-End Labeling; D007249:Inflammation / Q000139:chemically induced / Q000473:pathology; D017078:Laser-Doppler Flowmetry; D051379:Mice; D018345:Mice, Knockout; D008833:Microcirculation / Q000502:physiology; D018613:Microscopy, Confocal; D036641:Microscopy, Fluorescence, Multiphoton; D009474:Neurons / Q000502:physiology*; D020286:Pericytes / Q000502:physiology*; D010641:Phenotype; D020797:Receptor, Platelet-Derived Growth Factor beta / Q000235:genetics
D020797:Receptor, Platelet-Derived Growth Factor beta