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<p>Proteomic studies have identified thousands of protein changes in human Alzheimer’s disease brain tissue, offering significant opportunities for therapeutic and biomarker discovery. In this review, we discuss the current proteomic landscape of Alzheimer’s disease brain tissue, detailing protein changes across disease stages, brain regions, and neuropathological lesions (amyloid plaques, neurofibrillary tangles and cerebral amyloid angiopathy). By performing a combined analysis of 53 proteomics studies of human Alzheimer’s disease brain tissue, we highlight proteins of particular interest for future studies including highly reproducible protein changes across many studies, proteins altered in preclinical Alzheimer’s disease, and proteins significantly enriched in neuropathological lesions. This combined analysis revealed early synaptic vulnerability, progressive mitochondrial dysfunction and glial activation, and the prominent involvement of extracellular, glycosaminoglycan-binding proteins in amyloid plaques. We discuss key considerations for prioritising proteomic hits for drug discovery including disease relevance, safety considerations, assayability, and how protein structure can influence druggability. We discuss the careful consideration required for selecting an appropriate animal or cell model of Alzheimer’s disease for functional studies of proteomic hits and drug screening. We detail the strengths and limitations of several commonly used Alzheimer’s disease models including transgenic mouse models, iPSC derived cells, 3D cell cultures, organoids and emerging neurovascular organ-on-a-chip systems. Together, this review outlines a roadmap for translating proteomic discoveries into clinically meaningful therapies.</p>

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Translating Alzheimer’s disease proteomics into drug discovery opportunities

  • 期刊论文

  • 出版模式：

    开放获取

  • 发表日期：

    2026年6月15日

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  • Eleanor Drummond,
  • Eryn L. Werry,
  • Tomas Kavanagh,
  • Sian Genoud,
  • Ann Na Cho,
  • Shihui Chen,
  • Jonathan Du,
  • David Hibbs,
  • Michael Kassiou

摘要

Proteomic studies have identified thousands of protein changes in human Alzheimer’s disease brain tissue, offering significant opportunities for therapeutic and biomarker discovery. In this review, we discuss the current proteomic landscape of Alzheimer’s disease brain tissue, detailing protein changes across disease stages, brain regions, and neuropathological lesions (amyloid plaques, neurofibrillary tangles and cerebral amyloid angiopathy). By performing a combined analysis of 53 proteomics studies of human Alzheimer’s disease brain tissue, we highlight proteins of particular interest for future studies including highly reproducible protein changes across many studies, proteins altered in preclinical Alzheimer’s disease, and proteins significantly enriched in neuropathological lesions. This combined analysis revealed early synaptic vulnerability, progressive mitochondrial dysfunction and glial activation, and the prominent involvement of extracellular, glycosaminoglycan-binding proteins in amyloid plaques. We discuss key considerations for prioritising proteomic hits for drug discovery including disease relevance, safety considerations, assayability, and how protein structure can influence druggability. We discuss the careful consideration required for selecting an appropriate animal or cell model of Alzheimer’s disease for functional studies of proteomic hits and drug screening. We detail the strengths and limitations of several commonly used Alzheimer’s disease models including transgenic mouse models, iPSC derived cells, 3D cell cultures, organoids and emerging neurovascular organ-on-a-chip systems. Together, this review outlines a roadmap for translating proteomic discoveries into clinically meaningful therapies.