Early-life cognitive intervention preserves brain function in aged TgF344-AD rats with sex-specific effects
Alzheimer's disease is characterized by progressive cognitive decline, and its effects are mitigated by cognitive reserve. We investigated whether long-term cognitive stimulation, initiated before amyloid deposition, preserves brain function in male and female TgF344-AD rats. Transgenic and wild-type (WT) rats underwent cognitive training or remained untrained. Resting-state fMRI assessed functional connectivity, the novel object recognition test evaluated memory, and molecular analyses examined synaptic plasticity, inhibitory signaling, and microglial reactivity. At baseline, females showed greater task engagement and higher synaptic protein levels (PSD95, TrkB, and VGLUT) than males. Cognitive training improved connectivity and memory in males, with limited benefits in females. At 19 months, trained transgenic rats maintained entorhinal-hippocampal connectivity resembling WT rats, with males showing sustained plasticity markers and reduced parvalbumin-positive interneurons. Trained 11-month-old rats showed enhanced microglial recruitment to plaques and a less reactive phenotype. Overall, early and sustained cognitive stimulation enhances brain resilience, with sex-specific mechanisms shaping outcomes.
Authors
- Laura Molina‐Porcel (ORCID: https://orcid.org/0000-0003-4068-8578)
- Emma Muñoz‐Moreno (ORCID: https://orcid.org/0000-0003-2104-7265)
- Cristina Malagelada (ORCID: https://orcid.org/0000-0001-7185-436X)
- Fernando Aguado (ORCID: https://orcid.org/0000-0002-0393-1308)
- Alberto Prats‐Galino (ORCID: https://orcid.org/0000-0002-2710-6433)
- Raúl Tudela (ORCID: https://orcid.org/0000-0001-5134-4784)
- Genís Campoy‐Campos (ORCID: https://orcid.org/0000-0002-4235-7628)
- Federico Varriano (ORCID: https://orcid.org/0000-0001-6742-4746)
- Xavier López-Gil (ORCID: https://orcid.org/0000-0002-7468-6717)
- Claudia García-González (ORCID: https://orcid.org/0000-0002-8422-230X)
- Guadalupe Sòria (ORCID: https://orcid.org/0000-0002-8344-0479)
- Julia Casanova-Pagola (ORCID: https://orcid.org/0009-0000-8128-3185)
- Elisa López-Bravo
- Enric Abellí-Deulofeu
Institutions
- Neurosciences Institute (US)
- Instituto de Salud Carlos III (ES)
- Biomedical Research Networking Center on Neurodegenerative Diseases (ES)
- Biomedical Research Networking Center in Bioengineering, Biomaterials and Nanomedicine (ES)
- Hospital Clínic de Barcelona (ES)
- Clínica Diagonal (ES)
- Institute for Research in Biomedicine (ES)
- Fundació Clínic per a la Recerca Biomèdica (ES)
- Consorci Institut D'Investigacions Biomediques August Pi I Sunyer (ES)
- Universitat de Barcelona (ES)
Publication Details
- Journal
- iScience
- Published
- 2025-12-09
- DOI
- https://doi.org/10.1016/j.isci.2025.114381
- Primary Topic
- Functional Brain Connectivity Studies
- Type
- article
- Field-Weighted Citation Impact
- 0.00