Glial activation is moderated by sex in response to amyloidosis but not to tau pathology

Ziel/Aim In vivoassessment of neuroinflammation by 18 kDa translocator protein positron-emission-tomography (TSPO-PET) ligands receives growing interest in preclinical and clinical research of neurodegenerative disorders. Recently, sex specific differences characterized by higher TSPO expression in females have been reported for cognitively normal humans, but sex has not yet been evaluated in rodent models of neurodegeneration and their controls. Thus, we aimed to investigate effects of sex on TSPO expression in amyloid and tau mouse models and wild-type (WT) controls.

Methodik/Methods Longitudinal ¹⁸F-GE-180 TSPO-PET data of App^NL-G-F(amyloid model), P301S (tau model) and C57Bl/6 (WT) mice were evaluated between two and ten months of age. App^NL-G-F received additional amyloid-PET (Aβ-PET). TSPO- and Aβ-PET were analyzed in the contrast of male and female mice. Cortical target-to-reference standardized-uptake-value-ratios SUVr served as PET read out.

Ergebnisse/Results WT mice did not show significant sex specific differences in TSPO-PET between 2 and 10 months. App^NL-G-Fmice revealed a distinct cortical increase of TSPO-PET from 2.5 to 10 months in female mice (+31%), whereas male mice only showed a small TSPO-PET increase (+6%, p < 0.005). Aβ-PET in the same App^NL-G-Fmice increased at equal levels (female: 5 vs. male: 5%, p = n.s.) for both sexes. P301S mice showed strong cortical increases of TSPO-PET (+28%) from 2 to 8.5 months of age, but no significant sex differences were observed (female: 25% vs. male: 36%, p = n.s.).

Schlussfolgerungen/Conclusions Female mice indicate a sex dependent elevation of glial activation in response to amyloidosis, but not to tau pathology. This could be related to sex dependent and sex independent glial activation pathways in presence of different protein deposition.