Abstract
While the higher prevalence of Alzheimer’s disease (AD) in women is clear, studies suggest that biological sex may also influence AD pathogenesis. However, mechanisms behind these differences are not clear. To investigate physiological differences between sexes at the cellular level in the brain, we investigated the intrinsic and synaptic properties of entorhinal cortex neurons in heterozygous 3xTg-AD mice of both sexes at the age of 20 months. This brain region was selected because of its early association with AD symptoms. First, we found physiological differences between male and female non-transgenic mice, providing indirect evidence of axonal alterations in old females. Second, we observed a transgene-dependent elevation of the firing activity, post-burst afterhyperpolarization (AHP), and spontaneous excitatory postsynaptic current (EPSC) activity, without any effect of sex. Third, the passive properties and the hyperpolarization-activated current (Ih) were altered by transgene expression only in female mice, whereas the paired-pulse ratio (PPR) of evoked EPSC was changed only in males. Fourth, both sex and transgene expression were associated with changes in action potential properties. Consistent with previous work, higher levels of Aβ neuropathology were detected in 3xTg-AD females, whereas tau deposition was similar. In summary, our results support the idea that aging and AD neuropathology differentially alter the physiology of entorhinal cortex neurons in males and females.
Highlights
The prevalence of Alzheimer’s disease (AD) is higher for women than men
This study investigated the effects of biological sex in the neuronal dysfunction induced by the development of AD-like pathologies in 20-month-old heterozygous Triple-transgenic model of AD (3xTg-AD) mice
The hypothesis of the present work was that different experimental conditions could unmask sex differences in the alterations of Entorhinal cortex (EC) neurons driven by transgene expression, as was observed in neurons of the frontal cortex
Summary
The prevalence of Alzheimer’s disease (AD) is higher for women than men. While this difference is mainly explained by the gap in longevity, there is evidence of disparity in pathological processes between sexes. AD pathology is more strongly associated with clinical dementia in women than in men [1,2,3,4,5]. The importance of risk factors is dependent on sex, with midlife diabetes and APOE ε4 allele even more strongly associated with AD in women [6,7,8]. Studies performed in 3xTg-AD mice consistently report higher Aß burden in females [17,18,19] and sex-dependent
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