Retinal proteome changes mirror brain pathology and reveal synaptic and cytoskeletal dysfunction in Alzheimer’s disease

作者：Jessica Santiago, Dovilė Pocevičiūtė, Teo Sällberg, Patrik Önnerfjord, The Netherlands Brain Bank, Jacob W. Vogel, Malin Wennström · 发表于：Acta Neuropathologica · 年份：2026 · DOI：10.1007/s00401-026-03054-x · 研究领域：Alzheimer's disease research and treatments、Retinal Development and Disorders、Glaucoma and retinal disorders

Visual dysfunction is increasingly recognized as an important feature of Alzheimer's disease, and substantial retinal changes have been documented across multiple studies. Yet the molecular changes underlying retinal neurodegeneration and which retinal protein signatures best track cerebral pathology remain incompletely defined. Here, we performed comprehensive mass spectrometry-based proteomics on paired retinal and hippocampal tissue from the same postmortem donors (8 AD, 8 non-demented controls) to identify disease-associated molecular signatures and assess their overlap between these tissues. Using a sequential dual-extraction protocol, we identified 372 differentially abundant retinal proteins in AD, including established APP-processing regulators (SORL1, BACE1) and synaptic proteins. Retinal proteomes clearly separated AD from controls in principal component analysis, indicating robust AD-related molecular differences in the retina. Notably, 87% of proteins were detected in both retina and hippocampus, with 64 differentially abundant proteins shared between tissues, some of which showed strong cross-tissue correlation. Several retinal proteins also correlated with neuropathological disease stage. Functional enrichment analysis revealed convergent alterations in synaptic organization, cytoskeletal dynamics, mitochondrial function, cell adhesion, and APP metabolism in both tissues. Cell-type mapping using single-cell retinal reference data indicated that most proteomic ch...