Transcriptional profiles of immature neurons in aged human hippocampus track Alzheimer’s pathology and cognitive resilience
Year: 2026
Type: article
Study design: Observational Study
Abstract: The existence and functional significance of immature neurons in the adult human brain, particularly in the context of neurodegenerative disorders, remain controversial. While rodent studies have highlighted active roles for adult-born immature neurons in the hippocampus under both healthy conditions and in Alzheimer’s disease (AD), evidence from the human brain is limited and lacks detailed molecular characterization. To address this gap, we performed single-nucleus RNA sequencing in aged healthy, AD and dementia-resilient human hippocampus to probe immature neuronal signatures and gene expression alterations associated with AD pathology and resilience. Employing a novel experimental and computational pipeline, we identified persistent populations of immature neurons across all donor groups, with transcriptional profiles distinct from both fetal counterparts and adult mature hippocampal neurons. These profiles were associated with ‘juvenile’ cellular functions, suggesting that the presence of these immature neuronal populations per se may actively contribute to maintaining homeostasis within the aged human hippocampus, a role that may be disrupted in AD. In the resilient brain, immature neurons were involved in transcriptional programs and intercellular interactions associated with anti-inflammatory, neurotrophic, neuroprotective, myelinating, anti-apoptotic and anti-amyloidogenic signaling pathways, suggesting active roles for the immature cells in enhancing cognitive resilience in the presence of AD pathology. Our findings reveal novel, putative physiological roles for immature neurons in the healthy and resilient adult human brain, and offer a resource for probing new strategies with potential functional relevance in AD.
Source: Cell stem cell
Authors: Giorgia Tosoni, Dilara Ayyildiz, Sarah Snoeck, Elena P. Moreno-Jiménez, Amber Penning, Estibaliz Santiago-Mujika, Olmo Ruiz Ormaechea, Hyunah Lee, Suresh Poovathingal, Kristofer Davie, Julien Bryois, Will Macnair, Jasper Anink, Luuk E. De Vries, Sahand Farmand, Erik Nutma, Dick F. Swaab, Eleonora Aronica, Jinte Middeldorp, Sandrine Thuret, Laurent Roybon, Onur Basak, Carlos P. Fitzsimons, Paul J. Lucassen, Evgenia Salta
Institutions: Netherlands Institute for Neuroscience, Van Andel Institute, King's College London, VIB-KU Leuven Center for Brain & Disease Research, Roche (Switzerland), Amsterdam UMC Location University of Amsterdam, Biomedical Primate Research Centre, Utrecht University, University Medical Center Utrecht, University of Amsterdam
Language: English
Subfield: Developmental Neuroscience
Field: Neuroscience
Domain: Life Sciences
Open Access status: hybrid
Estimated APC paid: $10,400
OpenAlex ID: W7155550000