title: Notch1 signaling modulates neuronal progenitor activity in the subventricular zone in response to aging and focal ischemia.
abstract: Neurogenesis diminishes with aging and ischemia-induced neurogenesis also occurs, but reduced in aged brain. Currently, the cellular and molecular pathways mediating these effects remain largely unknown. Our previous study has shown that Notch1 signaling regulates neurogenesis in subventricular zone (SVZ) of young adult brain after focal ischemia, but whether a similar effect occurs in aged normal and ischemic animals is unknown. Here, we used normal and ischemic aged rat brains to investigate whether Notch1 signaling was involved in the reduction of neurogenesis in response to aging and modulates neurogenesis in aged brains after focal ischemia. By Western blot, we found that Notch1 and Jagged1 expression in the SVZ of aged brain was significantly reduced compared with young adult brain. Consistently, the activated form of Notch1 (Notch intracellular domain; NICD) expression was also declined. Immunohistochemistry confirmed that expression and activation of Notch1 signaling in the SVZ of aged brain were reduced. Double or triple immunostaining showed that that Notch1 was mainly expressed in doublecortin (DCX)-positive cells, whereas Jagged1 was predominantly expressed in astroglial cells in the SVZ of normal aged rat brain. In addition, disruption or activation of Notch1 signaling altered the number of proliferating cells labeled by bromodeoxyuridine (BrdU) and DCX in the SVZ of aged brain. Moreover, ischemia-induced cell proliferation in the SVZ of aged brain was enhanced by activating the Notch1 pathway and was suppressed by inhibiting the Notch1 signaling. Reduced infarct volume and improved motor deficits were also observed in Notch1 activator-treated aged ischemic rats. Our data suggest that Notch1 signaling modulates the SVZ neurogenesis in aged brain in normal and ischemic conditions.
authors.affiliation: Department of Neurology, Second Affiliated Hospital, School of Medicine, Zhejiang University, No. 88, Jiefang Road, Hangzhou, Zhejiang, 310009, China; Department of Pharmacology & Neuroscience, Institute for Aging and Alzheimer's Disease Research, University of North Texas Health Science Center, 3500 Camp Bowie Boulevard, Fort Worth, TX, 76107, USA.
authors.forename: Fen
authors.initials: F
authors.lastname: Sun
authors.forename: XiaoOu
authors.initials: X
authors.lastname: Mao
authors.forename: Lin
authors.initials: L
authors.lastname: Xie
authors.forename: Meiping
authors.initials: M
authors.lastname: Ding
authors.forename: Bei
authors.initials: B
authors.lastname: Shao
authors.forename: Kunlin
authors.initials: K
authors.lastname: Jin
mesh_terms: D000375:Aging / Q000378:metabolism / Q000473:pathology*; D000818:Animals; D001522:Behavior, Animal; D002545:Brain Ischemia / Q000378:metabolism* / Q000473:pathology*; D002135:Calcium-Binding Proteins / Q000378:metabolism; D049109:Cell Proliferation; D002544:Cerebral Infarction / Q000473:pathology; D002552:Cerebral Ventricles / Q000473:pathology*; D000089662:Doublecortin Protein; D036341:Intercellular Signaling Peptides and Proteins / Q000378:metabolism; D000072100:Jagged-1 Protein; D008297:Male; D008565:Membrane Proteins / Q000378:metabolism; D058953:Neural Stem Cells / Q000378:metabolism*; D017434:Protein Structure, Tertiary; D051381:Rats; D011916:Rats, Inbred F344; D051880:Receptors, Notch / Q000737:chemistry / Q000378:metabolism*; D000072099:Serrate-Jagged Proteins; D015398:Signal Transduction
chemical_list: D002135:Calcium-Binding Proteins; C000714848:Dcx protein, rat; D000089662:Doublecortin Protein; D036341:Intercellular Signaling Peptides and Proteins; C000606275:Jag1 protein, rat; D000072100:Jagged-1 Protein; D008565:Membrane Proteins; D051880:Receptors, Notch; D000072099:Serrate-Jagged Proteins
keywords: Notch1 signaling pathway; aged rat brain; focal cerebral ischemia; neurogenesis