Spatial single-cell proteo-transcriptomic map of neuroimmunein Alzheimer’s brain

초록

Microglia play a crucial role in the structural remodeling of amyloid-beta (Aβ) plaques, and impaired plaquecompactionhasbeenlinkedtotheexacerbationofAlzheimer’sdisease(AD).Tofurtherelucidatethe molecularmechanismsgoverningmicroglialneuroprotectioninAD,wedevelopedanintegrativemulti-omics approach,incorporatingsingle-celltranscriptomicandproteomicanalyses.Usingthesingle-cellmicroHOLD proteomic method, we characterizedthe proteomic dynamics of distinct microglial subsets and integrated these findings with transcriptomic datasets encompassing 150,000 microglial cells from AD continuum models.SpatialmappingofmicroglialdistributionwasperformedusingtheMERFISHplatform,covering2.8 million cells. Notably, disease-associated microglia (DAMs) and activated response microglia (ARMs) exhibited distinct proteo-transcriptomic alterations under AD conditions. To further investigate microglia-mediated metabolic changes inAD progression,we employedMALDI-IMSto identifymetabolic signatures of microglial subsets associated with Aβ plaques and tau pathology. This comprehensive single-cell multi-omics framework provides novel insights into the functional heterogeneity of microglial subpopulationsandtheircontributionstoneuroprotectioninAD.