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Background  In vivo assessment of neuroinflammation by 18-kDa translocator protein positron-emission-tomography (TSPO-PET) ligands receives growing interest in preclinical and clinical research of neurodegenerative disorders. Higher TSPO-PET binding as a surrogate for microglial activation in females has been reported for cognitively normal humans, but such effects have not yet been evaluated in rodent models of neurodegeneration and their controls. Thus, we aimed to investigate the impact of sex on microglial activation in amyloid and tau mouse models and wild-type controls.    Methods  TSPO-PET ( 18 F-GE-180) data of C57Bl/6 (wild-type),  App   NL-G-F   (β-amyloid model), and P301S (tau model) mice was assessed longitudinally between 2 and 12 months of age. The  App   NL-G-F   group also underwent longitudinal β-amyloid-PET imaging (Aβ-PET;  18 F-florbetaben). PET results were confirmed and validated by immunohistochemical investigation of microglial (Iba-1, CD68), astrocytic (GFAP), and tau (AT8) markers. Findings in cerebral cortex were compared by sex using linear mixed models for PET data and analysis of variance for immunohistochemistry.    Results  Wild-type mice showed an increased TSPO-PET signal over time (female +23%, male +4%), with a significant sex × age interaction ( T  = − 4.171,  p  < 0.001). The Aβ model  App   NL-G-F   mice also showed a significant sex × age interaction ( T  = − 2.953,  p  = 0.0048), where cortical TSPO-PET values increased by 31% in female  App   NL-G-F   mice, versus only 6% in the male mice group from 2.5 to 10 months of age. Immunohistochemistry for the microglial markers Iba-1 and CD68 confirmed the TSPO-PET findings in male and female mice aged 10 months. Aβ-PET in the same  App   NL-G-F   mice indicated no significant sex × age interaction ( T  = 0.425,  p  = 0.673). The P301S tau model showed strong cortical increases of TSPO-PET from 2 to 8.5 months of age (female + 32%, male + 36%), without any significant sex × age interaction ( T  = − 0.671,  p  = 0.504), and no sex differences in Iba-1, CD68, or AT8 immunohistochemistry.    Conclusion  Female mice indicate sex-dependent microglia activation in aging and in response to amyloidosis but not in response to tau pathology. This calls for consideration of sex difference in TSPO-PET studies of microglial activation in mouse models of neurodegeneration and by extension in human studies.

Glial activation is moderated by sex in response to amyloidosis but not to tau pathology in mouse models of neurodegenerative diseases