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

Abstract

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 (18F-GE-180) data of C57Bl/6 (wild-type), AppNL-G-F (β-amyloid model), and P301S (tau model) mice was assessed longitudinally between 2 and 12 months of age. The AppNL-G-F group also underwent longitudinal β-amyloid-PET imaging (Aβ-PET; 18F-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 AppNL-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 AppNL-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 AppNL-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.

Pre-therapeutic microglia activation and sex determine therapy effects of chronic immunomodulation

“…Interestingly, we observed a pronounced sex effect on the pioglitazone treatment response in App NL-G-F mice. Vehicle-treated female App NL-G-F mice showed the previously reported stronger increase of TSPO expression when compared to their male littermates 29 , but PPARγ stimulation attenuated this increase in females while tending to exacerbate the course of neuroinflammation in males. This finding may be of remarkable significance, since some pioglitazone studies used only female mice 37 or did not declare the sex of mice 38 .…”

“…Next, we tested whether previously observed sex differences in TSPO expression in mouse brain 29 have an impact on the responses to PPARγ pharmacological stimulation. To this end, we used the novel APP knock-in model App NL-G-F 16 mice and performed longitudinal TSPO-PET imaging during chronic pioglitazone treatment in groups of female and male mice.…”

Pre-therapeutic Microglia Activation and Sex Determine Therapy Effects of Chronic Immunomodulation

“…Interestingly, we observed a pronounced sex effect on the pioglitazone treatment response in App NL-G-F mice. Vehicle-treated female App NL-G-F mice showed the previously reported stronger increase of TSPO expression when compared to their male littermates 12 , but PPARγ stimulation rectified this increase in females while exacerbating the course of neuroinflammation in males. This finding is of remarkable translation significance, since some pioglitazone studies used only female mice 25 or did not declare the sex of mice 26 .…”

“…Next, we tested whether previously observed sex differences in TSPO expression in mouse brain 12 have an impact on the responses to PPARγ pharmacological stimulation. To this end, we used the novel APP knock-in model App NL-G-F 13 mice and performed longitudinal TSPO-PET imaging during chronic pioglitazone treatment in groups of female and male mice.…”

Positron Emission Tomography in Animal Models of Alzheimer’s Disease Amyloidosis

“…RN wrote the manuscript and approved the submission. APP/PS1 mice [40,60,82,86,[246][247][248] 3×Tg mice [249] APP23 mice [37,60,190] Aged non-human primate TASTPM mice [250] APP/PS1 mice [73,251] [ 18 F]florbetaben, AV-1 PS2APP mice [61,252] APPswe mice [61,253] App NL-G-F mice [68,192,197,252,254] APPswe/PS1G384A mice [61] APP-SL70 mice [252,255] TgF334 rats [152] APP/PS1 mice [61,68,82,256] [ 11 C]AZD2184 APPswe mice [244] APP/PS1 mice [257] [ 18 F]flutafuranol AZD4694, NAV4694…”