2026-07-21T15:10:47Zhttps://repisalud.isciii.es/rest/oai/requestoai:repisalud.isciii.es:20.500.12105/96902025-06-13T08:34:15Zcom_20.500.12105_2052com_20.500.12105_2051col_20.500.12105_19617
Repisalud
author
Díaz-Moreno, María
author
Armenteros, Tomás
author
Gradari, Simona
author
Hortigüela, Rafael
author
García-Corzo, Laura
author
Fontán-Lozano, Ángela
author
Trejo, José Luis
author
Mira, Helena
funder
Ministerio de Educación (España)
funder
Ministerio de Economía y Competitividad (España)
2020-04-22T17:40:55Z
2020-04-22T17:40:55Z
2018
Proc Natl Acad Sci U S A. 2018 Nov 6;115(45):11625-11630.
10.1073/pnas.1813205115
1091-6490
0027-8424
Proceedings of the National Academy of Sciences of the United States of America
30352848
http://hdl.handle.net/20.500.12105/9690
Increasing age is the greatest known risk factor for the sporadic late-onset forms of neurodegenerative disorders such as Alzheimer's disease (AD). One of the brain regions most severely affected in AD is the hippocampus, a privileged structure that contains adult neural stem cells (NSCs) with neurogenic capacity. Hippocampal neurogenesis decreases during aging and the decrease is exacerbated in AD, but the mechanistic causes underlying this progressive decline remain largely unexplored. We here investigated the effect of age on NSCs and neurogenesis by analyzing the senescence accelerated mouse prone 8 (SAMP8) strain, a nontransgenic short-lived strain that spontaneously develops a pathological profile similar to that of AD and that has been employed as a model system to study the transition from healthy aging to neurodegeneration. We show that SAMP8 mice display an accelerated loss of the NSC pool that coincides with an aberrant rise in BMP6 protein, enhanced canonical BMP signaling, and increased astroglial differentiation. In vitro assays demonstrate that BMP6 severely impairs NSC expansion and promotes NSC differentiation into postmitotic astrocytes. Blocking the dysregulation of the BMP pathway and its progliogenic effect in vivo by intracranial delivery of the antagonist Noggin restores hippocampal NSC numbers, neurogenesis, and behavior in SAMP8 mice. Thus, manipulating the local microenvironment of the NSC pool counteracts hippocampal dysfunction in pathological aging. Our results shed light on interventions that may allow taking advantage of the brain's natural plastic capacity to enhance cognitive function in late adulthood and in chronic neurodegenerative diseases such as AD.
eng
Alzheimer’s disease
BMP signaling
Adult neurogenesis
Aging
Neural stem cells
Noggin rescues age-related stem cell loss in the brain of senescent mice with neurodegenerative pathology
research article
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NogginRescuesAgeRelated_2018.pdf
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NogginRescuesAgeRelated_2018.pdf.txt