Abstract
Microglial endolysosomal (dys)function is strongly implicated in neurodegeneration. 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 in human AD brain and that the onset of this state is emphasized in females. Cst7 (encoding protein Cystatin F) is among the most highly upregulated genes in these microglia. However, despite such striking and robust upregulation, the sex-specific 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-deficient 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-deficient microglia were less inflammatory and had a reduction in lysosomal burden but had no change in Aβ burden. This study has important implications for AD research, confirming the functional role of a gene which is commonly upregulated in disease models, but also raising crucial questions on sexual dimorphism in neurodegenerative disease and the interplay between endolysosomal and inflammatory pathways in AD pathology.
Competing Interest Statement
TLS-J receives funding as a scientific advisory board member/scientific consultant from three collaborating pharmaceutical companies - these had no involvement with the current work
