Temporal and Sex-Linked Protein Expression Dynamics in a Familial Model of Alzheimer's Disease

Mouse models of Alzheimer's disease (AD) show pro-gression through stages reflective of human pathology. Proteomics identification of temporal and sex-linked fac-tors driving AD-related pathways can be used to dissect initiating and propagating events of AD stages to develop biomarkers or design interventions. In the present study, we conducted label-free proteome measurements of mouse hippocampus tissue with variables of time (3, 6, and 9 months), genetic background (5XFAD versus WT), and sex (equal males and females). These time points are associated with well-defined phenotypes with respect to the following: A beta 42 plaque deposition, memory deficits, and neuronal loss, allowing correlation of proteome-based molecular signatures with the mouse model stages. Our data show 5XFAD mice exhibit increases in known human AD biomarkers as amyloid-beta peptide, APOE, GFAP, and ITM2B are upregulated across all time points/stages. At the same time, 23 proteins are here newly associated with Alzheimer's pathology as they are also dysregulated in 5XFAD mice. At a pathways level, the 5XFAD-specific upregulated proteins are significantly enriched for DNA damage and stress-induced senescence at 3-month only, while at 6-month, the AD-specific proteome signature is altered and significantly enriched for membrane traf-ficking and vesicle-mediated transport protein annota-tions. By 9-month, AD-specific dysregulation is also characterized by significant neuroinflammation with innate immune system, platelet activation, and hyper-reactive astrocyte-related enrichments. Aside from these temporal changes, analysis of sex-linked differences in proteome signatures uncovered novel sex and AD -associated proteins. Pathway analysis revealed sex -linked differences in the 5XFAD model to be involved in the regulation of well-known human AD-related processes of amyloid fibril formation, wound healing, lysosome biogenesis, and DNA damage. Verification of the discovery results by Western blot and parallel reaction monitoring confirm the fundamental conclusions of the study and poise the 5XFAD model for further use as a molecular tool for understanding AD.

Automated summary

Mouse models of Alzheimer's disease can be used to study the progression of the disease and identify factors that drive AD-related pathways. This study used proteomics to analyze the hippocampus tissue of mice at different time points and with different genetic backgrounds and sexes. The results showed that 5XFAD mice exhibited increases in known AD biomarkers and also identified new proteins associated with AD pathology. Pathway analysis revealed sex-linked differences in the 5XFAD model related to amyloid fibril formation, wound healing, lysosome biogenesis, and DNA damage.