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However, the molecular composition of these plaques and their temporal regulation are not well defined. Here, we developed a sensitive workflow for quantitative proteomic profiling of single plaques using refined laser capture microdissection and data-independent acquisition mass spectrometry (LCM-DIA-MS). From &gt;200 plaques and control regions in AD mouse models (5xFAD and APP-KI) and human brains, we quantified &gt;7,000 proteins, revealing stage-dependent, cell-type-related remodeling of the amyloid proteome (amyloidome). Temporal profiling uncovered early immune and lysosomal activation followed by engagement of RNA processing and synaptic pathways. Cross-model and cross-species analyses determined a conserved amyloidome including APOE, MDK, PTN, and HTRA1, validated by co-localization in imaging analysis. Network analysis highlighted modules in lipid transport, vesicle organization, and autophagy. These findings establish amyloid plaques as conserved, dynamic multicellular hubs that link amyloid accumulation to downstream cellular events.<\/jats:p>","DOI":"10.64898\/2026.02.02.703320","type":"posted-content","created":{"date-parts":[[2026,2,5]],"date-time":"2026-02-05T00:10:11Z","timestamp":1770250211000},"source":"Crossref","is-referenced-by-count":1,"title":["Single Plaque Proteomics Reveals the Composition and Dynamics of the Amyloid Microenvironment in Alzheimer\u2019s Disease"],"prefix":"10.64898","author":[{"given":"Mengqi","family":"Chu","sequence":"first","affiliation":[{"name":"Department of Structural Biology, St. Jude Children\u2019s Research Hospital, Memphis, TN 38105, USA"},{"name":"Department of Developmental Neurobiology, St. Jude Children\u2019s Research Hospital, Memphis, TN 38105, 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