SEX-AND STAGE-DEPENDENT IMPAIRMENTS OF SYNAPTIC AND COGNITIVE HIPPOCAMPAL FUNCTION IN THE 5XFAD MODEL OF ALZHEIMER’S DISEASE: MECHANISTIC INSIGHTS FROM SPATIAL PROTEOMICS

In the early stages of Alzheimer’s disease (AD), hippocampal dysfunction emerges as a prominent neuropathological hallmark linked to the increase of amyloid-β (Aβ) peptide. In the 5xFAD mouse model of AD, characterized by mutant forms of amyloid precursor protein and presenilin-1 overexpression that leads to Aβ accumulation, hippocampal dysfunction begins around 1.5-3 months. While previous studies have explored this dysfunction, a significant gap remains in understanding its sex-dependent progression and differences at behavioral, synaptic, and molecular/proteomic levels, together with their subsequent differential neuroprotection mechanisms.
Here, we characterized sex-dependent progression in 3 and 6 month-old across synaptic, behavioral, and molecular levels. Synaptic function was assessed through CA3–CA1 long-term potentiation (LTP), paired-pulse facilitation (PPF), and excitability by spike-detection in hippocampal slices. Behavioral alterations were evaluated using the object location memory task to assess hippocampal-dependent spatial memory.. Spatial proteomic alterations were examined using MALDI imaging to analyze differential protein expression and spatial distribution within the CA1 hippocampal region.
Our results reveal marked sex differences in AD progression with 3-month males exhibiting impairments across synaptic and behavioral levels, whereas females remained unaffected. By 6 months, deficits emerged in females, while impairments in males persisted. Notably, we identified sex-specific proteins in CA1 that may contribute to preserved cognitive function in females at early stages. Together, these findings highlight sex as a critical determinant of early AD progression and suggest stage-dependent protein-associated neuroprotection in females that could lead sex-specific therapeutic strategies for AD .
Acknowledgements: MCIN/AEI/10.13039/501100011033(PID2020-115823-GBI00;PID2024-155413NB-I00), JCCM/FEDER(SBPLY/21/180501/000150;SBPLY/24/180225/000181), UCLM/FEDER(2022-GRIN-34354;2025-GRIN-38530) to JDNL/LJD.