Cystatin F(Cst7)drives sex-dependent changes in microglia in an amyloid-driven model of Alzheimer’s Disease

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 ofCst7in neurodegenerative disease is not understood. Here, we crossedCst7-/-mice with theAppNL-G-Fmouse to test the role ofCst7in a model of amyloid-driven AD. Surprisingly, we found thatCst7plays 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) burdenin vivoand were more phagocyticin 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.

Monocytes release cystatin F dimer to associate with Aβ and aggravate amyloid pathology and cognitive deficits in Alzheimer’s disease

“…Second, sex differences exist in clinical AD, and preclinical model animals also exhibit sexual dimorphisms in AD-like behaviours. In particular, Daniels MJD et al recently reported that cystatin F plays a sexually dimorphic role in regulating microglia in Cst7-deficient AD mice and that the microglia of female mice have a greater Aβ burden in vivo [77]. To avoid the potential confounding effects of sex, only male mice were used in this study.…”

Microglial senescence contributes to female-biased neuroinflammation in the aging mouse hippocampus: implications for Alzheimer’s disease

“…Cst7 is a marker of the DAM/ARM/MGnD phenotype (18, 49, 50) and involved in endolysosomal processing through inhibition of cysteine proteases (i.e., cathepsin L and C) (56). Interestingly, Cst7 knockout had sexually divergent effects on microglia in the APP NL-G-F mouse model of AD (57). Specifically, Cst7 knockout in APP NL-G-F mice led to upregulation of endolysosomal genes in females and downregulation of inflammatory genes in males.…”