Single cell transcriptome analysis of the THY-Tau22 mouse model of Alzheimer’s disease reveals sex-dependent dysregulations#

Authors#

Muhammad Ali, Pierre Garcia, Laetitia P. Lunkes, Alessia Sciortino, Melanie Thomas, Tony Heurtaux, Kamil Grzyb, Rashi Halder, Alexander Skupin, Luc Buée, David Blum, Manuel Buttini, Enrico Glaab

Abstract#

Abstract: Alzheimer’s disease (AD) is characterized by the accumulation of amyloid-beta and tau proteins in vulnerable brain regions. While the main pathological hallmarks of AD are shared across the sexes, a diverse array of sex differences have been documented in relation to both AD-associated symptoms and molecular characteristics. To gain insights into AD-associated molecular changes and their sex-dependence for tau-associated pathologies in the cortex as one of the most severely affected brain regions, we performed single-cell gene activity profiling in the THY-Tau22 mouse model. By studying cell-type specific and cell-type agnostic AD-related changes and their sex-dimorphism for single genes, pathways and cellular sub-networks, we aimed to identify both statistically significant alterations and interpret the upstream mechanisms that control them. Our results confirm several significant sex-dependent gene activity changes in the THY-Tau22 model mice compared to controls, including changes shared across multiple cell types and changes unique to particular cell types. The differential genes displayed a significant over-representation among the members of known AD-relevant cellular processes, e.g., pathways associated with neuronal differentiation, programmed cell death and inflammatory responses. The regulatory network analysis of these genes revealed upstream regulators which modulate many of the downstream target genes that display sex-dependent changes in the THY-Tau22 model. Most of the main regulators have previously already been implicated in AD, such as Egr1, Klf4, Chchd2, complement system genes, and myelin-associated glycoproteins. We also compared our findings from this study against the ones reported in the neocortex of Tg2576 AD mouse model and post-mortem human brain tissues from the entorhinal cortex and found 5 unique genes (MBP, MALAT1, PLP1, HSP90AA1, and ACTB) to be commonly differentially expressed across all three datasets in a cell type-specific manner. In summary, we observed statistically significant cell-type specific changes across several genes, pathways and sub-networks in the THY-Tau22 mouse model, with a strong over-representation of known AD-associated genes and processes. These changes include both sex-neutral and several sex-specific and sex-dimorphic patterns, with consistent and mechanistically interpretable alterations in upstream master regulators and their downstream target genes. Overall, these findings provide insights into the potential molecular mechanisms driving sex-specific susceptibility to AD, and reveal key regulatory proteins that may serve as targets for the development of pharmacological strategies to address sex-dependent pathology in AD.