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Targeted neuronal reprogramming rescues memory and neural synchrony in Alzheimer's disease.

Λεπτομέρειες βιβλιογραφικής εγγραφής
Τίτλος: Targeted neuronal reprogramming rescues memory and neural synchrony in Alzheimer's disease.
Συγγραφείς: Galán-Ganga M; Departament de Biomedicina, Facultat de Medicina, Institut de Neurociències, Universitat de Barcelona, Barcelona, 08036, Spain.; Institut d'Investigacions Biomèdiques August Pi I Sunyer (IDIBAPS), Barcelona, 08036, Spain.; Centro de Investigación Biomédica en Red Sobre Enfermedades Neurodegenerativas (CIBERNED), Madrid, 28031, Spain., Rodríguez-Navarro I; Departament de Biomedicina, Facultat de Medicina, Institut de Neurociències, Universitat de Barcelona, Barcelona, 08036, Spain.; Institut d'Investigacions Biomèdiques August Pi I Sunyer (IDIBAPS), Barcelona, 08036, Spain.; Centro de Investigación Biomédica en Red Sobre Enfermedades Neurodegenerativas (CIBERNED), Madrid, 28031, Spain., Zaballa S; Departament de Biomedicina, Facultat de Medicina, Institut de Neurociències, Universitat de Barcelona, Barcelona, 08036, Spain.; Institut d'Investigacions Biomèdiques August Pi I Sunyer (IDIBAPS), Barcelona, 08036, Spain.; Centro de Investigación Biomédica en Red Sobre Enfermedades Neurodegenerativas (CIBERNED), Madrid, 28031, Spain., Ramón-Lainez A; Departament de Biomedicina, Facultat de Medicina, Institut de Neurociències, Universitat de Barcelona, Barcelona, 08036, Spain.; Institut d'Investigacions Biomèdiques August Pi I Sunyer (IDIBAPS), Barcelona, 08036, Spain.; Centro de Investigación Biomédica en Red Sobre Enfermedades Neurodegenerativas (CIBERNED), Madrid, 28031, Spain., Gómez-Rivada N; Departament de Biomedicina, Facultat de Medicina, Institut de Neurociències, Universitat de Barcelona, Barcelona, 08036, Spain.; Institut d'Investigacions Biomèdiques August Pi I Sunyer (IDIBAPS), Barcelona, 08036, Spain.; Centro de Investigación Biomédica en Red Sobre Enfermedades Neurodegenerativas (CIBERNED), Madrid, 28031, Spain., Peters C; Department of Molecules-Signaling-Development, Max-Planck Institute for Biological Intelligence, Martinsried, 82152, Germany., Fernández-Irigoyen J; Proteomics Platform, Navarrabiomed, Hospital Universitario de Navarra (HUN), Universidad Pública de Navarra UPNA, IdiSNA, Pamplona, 31008, Spain., Santamaría E; Proteomics Platform, Navarrabiomed, Hospital Universitario de Navarra (HUN), Universidad Pública de Navarra UPNA, IdiSNA, Pamplona, 31008, Spain., Rabadán MÁ; ZeClinics SL. and ZeNeuroid SL., Barcelona, Spain., Alberch J; Departament de Biomedicina, Facultat de Medicina, Institut de Neurociències, Universitat de Barcelona, Barcelona, 08036, Spain.; Institut d'Investigacions Biomèdiques August Pi I Sunyer (IDIBAPS), Barcelona, 08036, Spain.; Centro de Investigación Biomédica en Red Sobre Enfermedades Neurodegenerativas (CIBERNED), Madrid, 28031, Spain.; Production and Validation Centre of Advanced Therapies (Creatio), Faculty of Medicine and Health Science, University of Barcelona, Barcelona, 08036, Spain., Rodríguez MJ; Departament de Biomedicina, Facultat de Medicina, Institut de Neurociències, Universitat de Barcelona, Barcelona, 08036, Spain.; Institut d'Investigacions Biomèdiques August Pi I Sunyer (IDIBAPS), Barcelona, 08036, Spain.; Centro de Investigación Biomédica en Red Sobre Enfermedades Neurodegenerativas (CIBERNED), Madrid, 28031, Spain., Del Toro D; Departament de Biomedicina, Facultat de Medicina, Institut de Neurociències, Universitat de Barcelona, Barcelona, 08036, Spain. danieldeltoro@ub.edu.; Institut d'Investigacions Biomèdiques August Pi I Sunyer (IDIBAPS), Barcelona, 08036, Spain. danieldeltoro@ub.edu.; Centro de Investigación Biomédica en Red Sobre Enfermedades Neurodegenerativas (CIBERNED), Madrid, 28031, Spain. danieldeltoro@ub.edu.; Production and Validation Centre of Advanced Therapies (Creatio), Faculty of Medicine and Health Science, University of Barcelona, Barcelona, 08036, Spain. danieldeltoro@ub.edu., Giralt A; Departament de Biomedicina, Facultat de Medicina, Institut de Neurociències, Universitat de Barcelona, Barcelona, 08036, Spain. albertgiralt@ub.edu.; Institut d'Investigacions Biomèdiques August Pi I Sunyer (IDIBAPS), Barcelona, 08036, Spain. albertgiralt@ub.edu.; Centro de Investigación Biomédica en Red Sobre Enfermedades Neurodegenerativas (CIBERNED), Madrid, 28031, Spain. albertgiralt@ub.edu.; Production and Validation Centre of Advanced Therapies (Creatio), Faculty of Medicine and Health Science, University of Barcelona, Barcelona, 08036, Spain. albertgiralt@ub.edu.
Πηγή: Molecular biomedicine [Mol Biomed] 2026 Jun 10; Vol. 7 (1). Date of Electronic Publication: 2026 Jun 10.
Τύπος έκδοσης: Journal Article
Γλώσσα: English
Στοιχεία περιοδικού: Publisher: Springer Singapore Country of Publication: Singapore NLM ID: 9918283581406676 Publication Model: Electronic Cited Medium: Internet ISSN: 2662-8651 (Electronic) Linking ISSN: 26628651 NLM ISO Abbreviation: Mol Biomed Subsets: MEDLINE
Imprint Name(s): Original Publication: Singapore : Springer Singapore, [2020]-
Ιατρικοί όροι (MeSH): Alzheimer Disease*/physiopathology , Alzheimer Disease*/pathology , Alzheimer Disease*/metabolism , Alzheimer Disease*/genetics , Neurons*/metabolism , Neurons*/pathology , Memory* , Cellular Reprogramming*, Receptors, N-Methyl-D-Aspartate/metabolism ; Hippocampus/metabolism ; Hippocampus/pathology ; Focal Adhesion Kinase 2/metabolism ; tau Proteins/metabolism ; Animals ; Male ; Mice ; Female ; Disease Models, Animal ; Mice, Transgenic ; Humans
Περίληψη: Alzheimer's disease (AD) is the most prevalent neurodegenerative disorder and represents a major societal burden. Aging is the strongest risk factor for AD, and partial cellular reprogramming using Yamanaka factors (YFs) has recently emerged as a strategy to counteract age-associated dysfunction. However, the mechanisms by which partial reprogramming ameliorates AD-related phenotypes remain poorly defined. Here, we investigated whether targeted and intermittent expression of YFs in hippocampal neurons restores cognitive function and neural network integrity in the P301S mouse model of tauopathy. We first show that controlled YFs expression in hippocampal neurons increases excitatory synaptic transmission and enhances neural synchrony in GCaMP6-expressing neuronal networks. We then induced intermittent, neuron-specific YFs expression for six months in adult control and P301S mice. This intervention led to a sex-dependent improvement in cognitive and emotional behaviors in P301S mice, accompanied by a reduction in Tau pathology and partial restoration of epigenetic aging markers. At the molecular level, reprogramming restored the composition and signaling of N-methyl-D-aspartate receptor (NMDAR) macro-complexes, including key subunits and AD-associated risk factors such as proline-rich tyrosine kinase 2 (PYK2/PTK2B). Importantly, impaired hippocampal neural synchrony observed in P301S mice was also rescued. Together, these findings demonstrate that targeted, partial in vivo neuronal reprogramming reverses behavioral and network-level deficits in a mouse model of AD and identify NMDAR-associated signaling as a potential mechanistic mediator of this effect.
(© 2026. The Author(s).)
Competing Interests: Declarations. Ethics approval and consent to participate: Experimental animals were used in accordance with the ethical guidelines (Declaration of Helsinki and NIH Publication no. 85–23, revised 1985, European Community Guidelines, and approved by the UB (CEEA: 55/21) and regional government (Generalitat de Catalunya: 11559) ethical committees. Consent for publication: Not applicable. Competing interests: All author declared no conflict of interest.
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Grant Information: CIVP21A7024 Fundación Ramón Areces; CNS2022 - 135391 Ministerio de Ciencia e Innovación; PID2024-157024OB-I00 Ministerio de Ciencia e Innovación
Contributed Indexing: Keywords: Astrocytes; Dendritic spines; Memory; Microglia; PYK2; Yamanaka factors
Substance Nomenclature: 0 (Receptors, N-Methyl-D-Aspartate)
EC 2.7.10.2 (Focal Adhesion Kinase 2)
0 (tau Proteins)
EC 2.7.10.2 (Ptk2b protein, mouse)
Entry Date(s): Date Created: 20260610 Date Completed: 20260612 Latest Revision: 20260726
Update Code: 20260726
PubMed Central ID: PMC13253944
DOI: 10.1186/s43556-026-00481-w
PMID: 42268557
Βάση Δεδομένων: MEDLINE
Περιγραφή
ISSN:2662-8651
DOI:10.1186/s43556-026-00481-w