title: Pericyte loss influences Alzheimer-like neurodegeneration in mice.
abstract: Pericytes are cells in the blood-brain barrier that degenerate in Alzheimer's disease (AD), a neurological disorder associated with neurovascular dysfunction, abnormal elevation of amyloid β-peptide (Aβ), tau pathology and neuronal loss. Whether pericyte degeneration can influence AD-like neurodegeneration and contribute to disease pathogenesis remains, however, unknown. Here we show that in mice overexpressing Aβ-precursor protein, pericyte loss elevates brain Aβ40 and Aβ42 levels and accelerates amyloid angiopathy and cerebral β-amyloidosis by diminishing clearance of soluble Aβ40 and Aβ42 from brain interstitial fluid prior to Aβ deposition. We further show that pericyte deficiency leads to the development of tau pathology and an early neuronal loss that is normally absent in Aβ-precursor protein transgenic mice, resulting in cognitive decline. Our data suggest that pericytes control multiple steps of AD-like neurodegeneration pathogenic cascade in Aβ-precursor protein-overexpressing mice. Therefore, pericytes may represent a novel therapeutic target to modify disease progression in AD.
authors: 1] Department of Physiology and Biophysics, Keck School of Medicine, Zilkha Neurogenetic Institute, University of Southern California, Los Angeles, California 90033, USA [2].
authors: Abhay P
authors: AP
authors: Sagare
authors: 1] Center of Neurodegenerative and Vascular Brain Disorders, University of Rochester Medical Center, Rochester, New York 14642, USA [2].
authors: Robert D
authors: RD
authors: Bell
authors: 1] Department of Physiology and Biophysics, Keck School of Medicine, Zilkha Neurogenetic Institute, University of Southern California, Los Angeles, California 90033, USA [2].
authors: Zhen
authors: Z
authors: Zhao
authors: Department of Physiology and Biophysics, Keck School of Medicine, Zilkha Neurogenetic Institute, University of Southern California, Los Angeles, California 90033, USA.
authors: Qingyi
authors: Q
authors: Ma
authors: Center of Neurodegenerative and Vascular Brain Disorders, University of Rochester Medical Center, Rochester, New York 14642, USA.
authors: Ethan A
authors: EA
authors: Winkler
authors: Department of Physiology and Biophysics, Keck School of Medicine, Zilkha Neurogenetic Institute, University of Southern California, Los Angeles, California 90033, USA.
authors: Anita
authors: A
authors: Ramanathan
authors: Department of Physiology and Biophysics, Keck School of Medicine, Zilkha Neurogenetic Institute, University of Southern California, Los Angeles, California 90033, USA.
authors: Berislav V
authors: BV
authors: Zlokovic
mesh_terms: D000544:Alzheimer Disease / Q000473:pathology; D016229:Amyloid beta-Peptides / Q000378:metabolism; D016564:Amyloid beta-Protein Precursor / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D001921:Brain / Q000378:metabolism / Q000473:pathology; D016923:Cell Death; D051379:Mice; D008822:Mice, Transgenic; D019636:Neurodegenerative Diseases / Q000473:pathology*; D009474:Neurons / Q000473:pathology; D010446:Peptide Fragments / Q000378:metabolism; D020286:Pericytes / Q000473:pathology*; D010766:Phosphorylation; D016875:tau Proteins / Q000378:metabolism
chemical_list: D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; C558298:Mapt protein, mouse; D010446:Peptide Fragments; C078592:amyloid beta-protein (1-40); C075222:amyloid beta-protein (1-42); D016875:tau Proteins