gms | German Medical Science

Introduction & Objectives: Epidemiologic studies indicate a higher female prevalence for Alzheimer’s disease (AD) but the reason for this sex preference is not well understood. Here, we systematically determined sex-specific differences in the course of the disease in transgenic (Tg) mice with the ultimate goal to uncover molecular mechanisms that might contribute to these sex-specific differences.

Materials & Methods: Male and female TgCRND8 mice were characterized for Aβ plaque burden, APP metabolism, and tau pathology around disease onset (P90), in a moderate (P180) and in an advanced disease stage (P360). Furthermore, we assessed sex-specific differences in cognitive performance, structural plasticity, neurovascular function, neuroinflammation, and autophagy in diseased (and healthy) mice. Additionally, cerebral levels of Kallikrein-8 (KLK8), a serine protease that is excessively expressed in AD-affected human and murine brain (see abstract no. 16), of the KLK8 substrate Ephrin receptor B2 (EPHB2) and of the neurosteroid allopregnanolone were recorded.

Results: Already around disease onset at P90 there was an increased Aβ plaque load in female mice in comparison to males. This sex-specific difference aggravated until P360, whereas APP expression and processing remained unchanged and equal across all ages and both sexes. Subsequent to increased Aβ plaque pathology a worse quality of cognitive performance, neurovascular function and higher levels of neuroinflammation became evident in female mice when compared to males first at P360. Tau pathology, structural plasticity, autophagy, and allopregnanolone levels were similarly affected in both sexes until P360. Remarkably, the per se increased KLK8 level in Tg mice (when compared to wildtypes) turned out to be higher in diseased females than males already at P30. This sex-specific difference progressively grew until P360, followed by a lower level of its (per se in Tg mice depleted) substrate EPHB2 around P360.

Conclusions: Multiple pathological features of AD are more pronounced in female than in male mice. These sex-specific differences take varying periods of time to evolve – all of which weeks or months after emergence of cerebral KLK8 excess. Yet early KLK8 overexpression might be a causative element for the preferential female prevalence of AD.