In-Depth Proteomic Analysis of De Novo Proteome in a Mouse Model of Alzheimer's Disease

Background: Alzheimer's disease (AD) is the most common dementia syndrome in the elderly characterized by synaptic failure and unique brain pathology. De novo protein synthesis is required for the maintenance of memory and synaptic plasticity. Mounting evidence links impaired neuronal protein synthesis capacity and overall protein synthesis deficits to AD pathogenesis. Meanwhile, identities of AD-associated dysregulation of newly synthesized proteome remain elusive. Objective: To investigate de novo proteome alterations in the hippocampus of aged Tg19959 AD model mice. Methods: In this study, we combined the bioorthogonal noncanonical amino acid tagging (BONCAT) method with the unbiased large-scale proteomic analysis in acute living brain slices (we name it BONSPEC) to investigate de novo proteome alterations in the hippocampus of Tg19959 AD model mice. We further applied multiple bioinformatics methods to analyze in-depth the proteomics data. Results: In total, 1,742 proteins were detected across the 10 samples with the BONSPEC method. After exclusion of those only detected in less than half of the samples in both groups, 1,362 proteins were kept for further analysis. 37 proteins were differentially expressed (based on statistical analysis) between the WT and Tg19959 groups. Among them, 19 proteins were significantly decreased while 18 proteins were significantly increased in the hippocampi of Tg19959 mice compared to WT mice. The results suggest that proteins involved in synaptic function were enriched in de novo proteome of AD mice. Conclusion: Our study could provide insights into the future investigation into the molecular signaling mechanisms underlying AD and related dementias (ADRDs).

Automated summary

This study investigated de novo proteome alterations in the hippocampus of aged Tg19959 AD model mice using the BONCAT method combined with unbiased large-scale proteomic analysis (BONSPEC). Multiple bioinformatics methods were applied to analyze the proteomics data, revealing an enrichment of proteins involved in synaptic function in the de novo proteome of AD mice. This study provides insights into the molecular signaling mechanisms underlying AD and related dementias (ADRDs).