All‐in‐Human Target Discovery in Alzheimer’s Disease and Resilient Brains

Abstract

AbstractBackgroundAlzheimer’s disease (AD) is characterized by neuropathological hallmarks including amyloid plaques and tau tangles and neurodegeneration in the frontal cortex. While there is a strong association of tau pathology with neurodegeneration and cognitive decline, around 30% of amyloid plaque‐carrying seniors remain cognitively healthy. We hypothesize that protective cellular mechanisms upstream of tau phosphorylation and neurodegeneration may underlie this resilience.MethodWe applied high resolution spatial transcriptomics and single nuclei RNA sequencing on postmortem frontal lobes from 10 demented and 10 non‐demented individuals with comparable degrees of amyloid pathology. We integrated the generated transcriptomics data with proteomics, genomics and drug action databases and interpret cellular transcriptome responses to pathology in the context of human specific protein‐protein interaction networks.ResultUsing spatial and single nuclei transcriptomics, we identify specific transcriptomic signatures and regulatory networks in cellular microenvironments around amyloid plaques and pTau pathology niches. Our results suggest that specific neuronal and glial subpopulations carry enriched vulnerability towards amyloid plaque and pTau depositions. We further find that certain cell death signaling pathways related to neurodegeneration are overrepresented in the context of pTau pathology. Finally, our multi‐omics database integration approach has led to the identification of potential drug targets for therapeutics addressing cellular mechanisms of neuroprotection.ConclusionSpatial transcriptomics from human brain tissue is a powerful approach to reveal cellular mechanisms of pathogenic lesions and enables us to identify neuroprotective mechanisms that may prevent the development of tauopathy and ultimately neuronal loss. The combination of single cell and spatial transcriptomics together with protein‐protein interaction networks provides a promising approach for the identification of novel therapeutic targets for AD.