Sex-dependent Hippocampal Astrocytic Signaling and Synaptic Alterations Associated With Behavioral Impairments in...

Sporadic Alzheimer's disease (AD) disproportionately affects women, yet sex differences in disease mechanisms remain incompletely understood, raising the question of whether preclinical models such as the intracerebroventricular (ICV) streptozotocin (STZ) model adequately capture sex-dependent differences. We examined whether STZ-induced alterations are similarly expressed in males and females and whether ovarian hormones modulate vulnerability to STZ. Three-month-old Sprague-Dawley male, intact female, and ovariectomized (OVX) female rats received ICV artificial cerebrospinal fluid or STZ (3 mg/kg). Behavioral testing was conducted 14-24 days post-injection, followed by hippocampal analyses. STZ increased depressive-like behavior and reduced species-typical burying behavior overall (both p < 0.0001), whereas recognition memory performance did not differ significantly between groups. Spatial memory was more impaired in STZ-treated males, which showed increased Barnes maze latency (p = 0.0027) and fewer head entries into the goal sector (p = 0.0315) than male controls. STZ also reduced PSA-NCAM-positive cells across groups (p < 0.0001) and increased GFAP expression in CA3 (p = 0.0401). Nuclear STAT3 activation increased in STZ-treated males in CA3 (p = 0.004), CA1 (p = 0.0323), and dentate gyrus (p = 0.0058), while synaptic density in the CA3 stratum lucidum was reduced in STZ-treated males (p = 0.0208). Ovarian hormone depletion did not increase female susceptibility to STZ for these key sex-dependent outcomes. Overall, males showed greater vulnerability to STZ-induced spatial memory deficits, astrocytic JAK/STAT3 activation, and synaptic loss, whereas both intact and ovariectomized females displayed an attenuated early phenotype. These findings indicate that the STZ-induced AD-like phenotype is not equivalently expressed across sexes and underscore sex as a critical variable in the translational interpretation of this model.