UK Dementia Research Institute at The University of Edinburgh, Edinburgh, United Kingdom; Centre for Inflammation Research, Institute for Regeneration and Repair, The University of Edinburgh, Edinburgh, United Kingdom
UK Dementia Research Institute at The University of Edinburgh, Edinburgh, United Kingdom; Simons Initiative for the Developing Brain, University of Edinburgh, Edinburgh, United Kingdom
UK Dementia Research Institute at The University of Edinburgh, Edinburgh, United Kingdom; Simons Initiative for the Developing Brain, University of Edinburgh, Edinburgh, United Kingdom
Mehreen Mohammad
UK Dementia Research Institute at The University of Edinburgh, Edinburgh, United Kingdom
Hiroki Sasaguri
Department of Neurology and Neurological Science, Graduate School of Medicine, Tokyo Medical and Dental University, Tokyo, Japan; Laboratory for Proteolytic Neuroscience, RIKEN Brain Science Institute, Wako, Japan
Takashi Saito
Laboratory for Proteolytic Neuroscience, RIKEN Brain Science Institute, Wako, Japan; Department of Neuroscience and Pathobiology, Research Institute of Environmental Medicine, Nagoya University, Nagoya, Japan; Department of Neurocognitive Science, Institute of Brain Science, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan
Takaomi C Saido
Laboratory for Proteolytic Neuroscience, RIKEN Brain Science Institute, Wako, Japan
Microglial endolysosomal (dys)function is strongly implicated in neurodegenerative disease. Transcriptomic studies show that a microglial state characterised by a set of genes involved in endolysosomal function is induced in both mouse Alzheimer’s disease (AD) models and human AD brain, and that the emergence of this state is emphasised in females. Cst7 (encoding cystatin F) is among the most highly upregulated genes in these microglia. However, despite such striking and robust upregulation, the function of Cst7 in neurodegenerative disease is not understood. Here, we crossed Cst7-/- mice with the AppNL-G-F mouse to test the role of Cst7 in a model of amyloid-driven AD. Surprisingly, we found that Cst7 plays a sexually dimorphic role regulating microglia in this model. In females, Cst7-/-AppNL-G-F microglia had greater endolysosomal gene expression, lysosomal burden, and amyloid beta (Aβ) burden in vivo and were more phagocytic in vitro. However, in males, Cst7-/-AppNL-G-F microglia were less inflammatory and had a reduction in lysosomal burden but had no change in Aβ burden. Overall, our study reveals functional roles for one of the most commonly upregulated genes in microglia across disease models, and the sex-specific profiles of Cst7-/--altered microglial disease phenotypes. More broadly, the findings raise important implications for AD including crucial questions on sexual dimorphism in neurodegenerative disease and the interplay between endolysosomal and inflammatory pathways in AD pathology.
