Yarbro Jay M, Han Xian, Dasgupta Abhijit, Yang Ka, Liu Danting, Shrestha Him K, Zaman Masihuz, Wang Zhen, Yu Kaiwen, Lee Dong Geun, Vanderwall David, Niu Mingming, Sun Huan, Xie Boer, Chen Ping-Chung, Jiao Yun, Zhang Xue, Wu Zhiping, Fu Yingxue, Li Yuxin, Yuan Zuo-Fei, Wang Xusheng, Poudel Suresh, Vagnerova Barbora, He Qianying, Tang Andrew, Ronaldson Patrick T, Chang Rui, Yu Gang, Liu Yansheng, Peng Junmin
Department of Structural Biology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA.
Department of Developmental Neurobiology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA.
bioRxiv. 2024 Oct 25:2024.10.25.620263. doi: 10.1101/2024.10.25.620263.
Murine models of Alzheimer's disease (AD) are crucial for elucidating disease mechanisms but have limitations in fully representing AD molecular complexities. We comprehensively profiled age-dependent brain proteome and phosphoproteome ( > 10,000 for both) across multiple mouse models of amyloidosis. We identified shared pathways by integrating with human metadata, and prioritized novel components by multi-omics analysis. Collectively, two commonly used models (5xFAD and APP-KI) replicate 30% of the human protein alterations; additional genetic incorporation of tau and splicing pathologies increases this similarity to 42%. We dissected the proteome-transcriptome inconsistency in AD and 5xFAD mouse brains, revealing that inconsistent proteins are enriched within amyloid plaque microenvironment (amyloidome). Determining the 5xFAD proteome turnover demonstrates that amyloid formation delays the degradation of amyloidome components, including Aβ-binding proteins and autophagy/lysosomal proteins. Our proteomic strategy defines shared AD pathways, identify potential new targets, and underscores that protein turnover contributes to proteome-transcriptome discrepancies during AD progression.
阿尔茨海默病（AD）的小鼠模型对于阐明疾病机制至关重要，但在全面呈现AD分子复杂性方面存在局限性。我们全面分析了多种淀粉样变性小鼠模型中随年龄变化的脑蛋白质组和磷酸化蛋白质组（两者均超过10,000种）。我们通过与人类元数据整合确定了共享途径，并通过多组学分析对新成分进行了优先级排序。总体而言，两种常用模型（5xFAD和APP-KI）复制了30%的人类蛋白质改变；tau和剪接病理的额外基因整合将这种相似性提高到了42%。我们剖析了AD和5xFAD小鼠大脑中蛋白质组-转录组的不一致性，发现不一致的蛋白质在淀粉样斑块微环境（淀粉样蛋白组）中富集。确定5xFAD蛋白质组的周转表明，淀粉样蛋白的形成延迟了淀粉样蛋白组成分的降解，包括Aβ结合蛋白和自噬/溶酶体蛋白。我们的蛋白质组学策略定义了共享的AD途径，识别了潜在的新靶点，并强调蛋白质周转在AD进展过程中导致了蛋白质组-转录组差异。
