Nerve growth factor receptor (Ngfr) induces neurogenic plasticity by suppressing reactive astroglial Lcn2/Slc22a17 signaling in Alzheimer’s disease

Publikation: Beitrag in FachzeitschriftForschungsartikelBeigetragenBegutachtung

Beitragende

  • Tohid Siddiqui - , Deutsches Zentrum für Neurodegenerative Erkrankungen (DZNE) (Autor:in)
  • Mehmet Ilyas Cosacak - , Professur für Neuronale Entwicklung und Regeneration, Deutsches Zentrum für Neurodegenerative Erkrankungen (DZNE) (Autor:in)
  • Stanislava Popova - , Deutsches Zentrum für Neurodegenerative Erkrankungen (DZNE) , Neuron D GmbH (Autor:in)
  • Prabesh Bhattarai - , Deutsches Zentrum für Neurodegenerative Erkrankungen (DZNE) , Columbia University (Autor:in)
  • Elanur Yilmaz - , Columbia University (Autor:in)
  • Annie J. Lee - , Columbia University (Autor:in)
  • Yuhao Min - , Mayo Clinic Jacksonville, FL (Autor:in)
  • Xue Wang - , Mayo Clinic Jacksonville, FL (Autor:in)
  • Mariet Allen - , Mayo Clinic Jacksonville, FL (Autor:in)
  • Özkan Iş - , Mayo Clinic Jacksonville, FL (Autor:in)
  • Zeynep Tansu Atasavum - , Deutsches Zentrum für Neurodegenerative Erkrankungen (DZNE) (Autor:in)
  • Natalia Rodriguez-Muela - , Selektive Neuronale Verwundbarkeit bei Neurodegenerativen Erkrankungen (NFoG), Deutsches Zentrum für Neurodegenerative Erkrankungen (DZNE) (Autor:in)
  • Badri N. Vardarajan - , Columbia University (Autor:in)
  • Delaney Flaherty - , Columbia University (Autor:in)
  • Andrew F. Teich - , Columbia University (Autor:in)
  • Ismael Santa-Maria - , Columbia University, Francisco de Vitoria University (Autor:in)
  • Uwe Freudenberg - , Leibniz-Institut für Polymerforschung Dresden (Autor:in)
  • Carsten Werner - , Professur für Elastomere Werkstoffe (g.B. IPF), Professur für Biofunktionale Polymermaterialien (gB/IPF), Technische Universität Dresden (Autor:in)
  • Giuseppe Tosto - , Columbia University (Autor:in)
  • Richard Mayeux - , Columbia University (Autor:in)
  • Nilüfer Ertekin-Taner - , Mayo Clinic Jacksonville, FL (Autor:in)
  • Caghan Kizil - , Klinik und Poliklinik für Neurologie, Mechanismen der induzierten Plastizität des Gehirns (FoG), Deutsches Zentrum für Neurodegenerative Erkrankungen (DZNE) , Columbia University, Taub Institute for Research on Alzheimer’s Disease and the Aging Brain (Autor:in)

Abstract

Neurogenesis, crucial for brain resilience, is reduced in Alzheimer’s disease (AD) that induces astroglial reactivity at the expense of the pro-neurogenic potential, and restoring neurogenesis could counteract neurodegenerative pathology. However, the molecular mechanisms promoting pro-neurogenic astroglial fate despite AD pathology are unknown. In this study, we used APP/PS1dE9 mouse model and induced Nerve growth factor receptor (Ngfr) expression in the hippocampus. Ngfr, which promotes neurogenic fate of astroglia during the amyloid pathology-induced neuroregeneration in zebrafish brain, stimulated proliferative and neurogenic outcomes. Histological analyses of the changes in proliferation and neurogenesis, single-cell transcriptomics, spatial proteomics, and functional knockdown studies showed that the induced expression of Ngfr reduced the reactive astrocyte marker Lipocalin-2 (Lcn2), which we found was sufficient to reduce neurogenesis in astroglia. Anti-neurogenic effects of Lcn2 was mediated by Slc22a17, blockage of which recapitulated the pro-neurogenicity by Ngfr. Long-term Ngfr expression reduced amyloid plaques and Tau phosphorylation. Postmortem human AD hippocampi and 3D human astroglial cultures showed elevated LCN2 levels correlate with reactive gliosis and reduced neurogenesis. Comparing transcriptional changes in mouse, zebrafish, and human AD brains for cell intrinsic differential gene expression and weighted gene co-expression networks revealed common altered downstream effectors of NGFR signaling, such as PFKP, which can enhance proliferation and neurogenesis in vitro when blocked. Our study suggests that the reactive non-neurogenic astroglia in AD can be coaxed to a pro-neurogenic fate and AD pathology can be alleviated with Ngfr. We suggest that enhancing pro-neurogenic astroglial fate may have therapeutic ramifications in AD.

Details

OriginalspracheEnglisch
Aufsatznummer33
Fachzeitschriftnpj Regenerative Medicine
Jahrgang8
Ausgabenummer1
PublikationsstatusVeröffentlicht - Juli 2023
Peer-Review-StatusJa

Externe IDs

ORCID /0000-0003-1065-1870/work/151438187
ORCID /0000-0003-0189-3448/work/159607216