Understanding the impact of genetic background on animal models of Alzheimer’s disease (AD) is crucial for improving their translational validity. Researchers have proposed introducing genetic diversity into AD mouse models to uncover new genetic factors contributing to AD susceptibility or resilience. In a recent study, scientists crossed the 5XFAD AD mouse model with different genetic backgrounds and analyzed the brain proteome of the resulting offspring. They discovered that both genetic background and the 5XFAD transgene strongly influenced protein variance in the hippocampus and cortex. Interestingly, certain protein modules associated with small molecule metabolism, ion transport, lysosome/stress response, and neuronal synapse/signaling were significantly affected by genetic background. However, modules directly linked to human disease, like neuronal synapse/signaling and lysosome/stress response modules, were not influenced by genetic background. This research highlights the importance of considering genetic diversity when analyzing AD mouse models and suggests that proteomic analysis of alternative genetic backgrounds should be explored. To delve deeper into the intricacies of genetically diverse AD models, check out the full research article!

There is an urgent need to improve the translational validity of Alzheimer’s disease (AD) mouse models. Introducing genetic background diversity in AD mouse models has been proposed as a way to increase validity and enable the discovery of previously uncharacterized genetic contributions to AD susceptibility or resilience. However, the extent to which genetic background influences the mouse brain proteome and its perturbation in AD mouse models is unknown. In this study, we crossed the 5XFAD AD mouse model on a C57BL/6J (B6) inbred background with the DBA/2J (D2) inbred background and analyzed the effects of genetic background variation on the brain proteome in F1 progeny. Both genetic background and 5XFAD transgene insertion strongly affected protein variance in the hippocampus and cortex (n = 3,368 proteins). Protein co-expression network analysis identified 16 modules of highly co-expressed proteins common across the hippocampus and cortex in 5XFAD and non-transgenic mice. Among the modules strongly influenced by genetic background were those related to small molecule metabolism and ion transport. Modules strongly influenced by the 5XFAD transgene were related to lysosome/stress responses and neuronal synapse/signaling. The modules with the strongest relationship to human disease—neuronal synapse/signaling and lysosome/stress response—were not significantly influenced by genetic background. However, other modules in 5XFAD that were related to human disease, such as GABA synaptic signaling and mitochondrial membrane modules, were influenced by genetic background. Most disease-related modules were more strongly correlated with AD genotype in the hippocampus compared with the cortex. Our findings suggest that the genetic diversity introduced by crossing B6 and D2 inbred backgrounds influences proteomic changes related to disease in the 5XFAD model, and that proteomic analysis of other genetic backgrounds in transgenic and knock-in AD mouse models is warranted to capture the full range of molecular heterogeneity in genetically diverse models of AD.

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