TO CONVERT OR NOT TO CONVERT: EARLY SEX-SPECIFIC VULNERABILITY AND RESILIENCE MARKERS IN ALZHEIMER’S MICE

Alzheimer's disease (AD) is a progressive neurodegenerative disorder for which there is currently no effective treatment, highlighting the urgent need for early diagnosis anticipating therapeutic interventions. The Tg2576 mouse model, which replicates the temporal progression of amyloid pathology and cognitive decline, is a valuable model for studying the mechanisms of AD onset. Leveraging on the six different objects test (6-DOT), which distinguishes the subjects that will convert or not convert to AD based on a subtle deficit in high memory load, this study aimed to compare how memory progressively deteriorates in Tg2576 mice of both sexes, and whether this deterioration depends on alterations in activity-induced structural plasticity in key memory brain regions. Male and female Tg2576 (Tg) mice aged 2, 4, and 6 months were subjected to the 6-DOT. Following the tests, the brains of the trained mice were processed to visualize dendritic spines using Golgi-Cox staining. We observed that transgenic males, unlike females, exhibited deficits in high-load memory as early as two months of age, when they are generally considered asymptomatic, and that these deficits persisted at four months of age. Immuno-histochemical analyses of the Golgi-stained neurons then revealed a prominent reduction in training-induced dendritic spines in the retrosplenial cortex of Tg males, but not of females. Our results highlight a male-specific deficit in retrosplenial spinogenesis associated with the first memory impairments, and underline the importance of identifying neurobiological markers of female resilience.