Systems analysis of Alzheimer’s disease pathway dysregulation in human subjects is recapitulated in 3d cellular models to reveal P38 MAPK as a therapeutic target that mitigates tau pathology

Background 3D human neural cell culture models of Alzheimer’s disease (AD) are valuable resources for studying AD pathogenesis mechanisms. Although our 3D models capture cellular heterogeneity and key pathogenic cascades in AD, including β‐amyloid (Aβ) accumulation and Aβ‐induced tau pathology, it is not known to what extent 3D models functionally reflect human AD pathogenesis. We address this gap by capturing functionally active AD pathways in human brain through a granular systems approach that accurately recapitulates the activity of disease‐associated pathways from afflicted brain tissues in 3D models. Methods We leveraged transcriptomic data to precisely determine the activity dynamics of biological pathways. We assembled transcriptomic data from AD brains and compared them with a battery of 3D models displaying a broad range of disease‐associated characteristics. Our approach discovered pathways showing concordant dysregulation patterns between human brain and disease models. We prioritized the most consistent AD‐pathways for in‐vitro therapeutic screening. Results One of our 3D models has transmembrane domain APP mutations, but not PS1 mutations and exhibits an elevated Aβ42/40 ratio. It best recapitulated dysregulated AD‐pathways found in both human prefrontal and temporal cortices. Multiple pathways indicated activation of p38 MAPK signaling, coupled with broad transcriptional inactivation in AD. Cellular and biochemical validations demonstrated elevated phosphorylated‐p38 (p‐tau)/total‐p38 ratios. Treatment with a p38 MAPK inhibitor resulted in significant reduction in the total amount of tau, significant reduction in the amount of p‐tau, and suggestive reduction in p‐tau/tau ratio. Our results strongly support a critical role for p38 MAPK signaling in mediating Ab‐induced tau pathology. Conclusions Using human brain transcriptomes, we have introduced a broadly‐applicable systems biology approach to rapidly discover therapeutic targets in 3D models. The approach provides a granular determination of the degree to which cellular models accurately reflect dysregulated molecular pathways in afflicted brains. We have detected, validated, and targeted the activated p38 MAPK pathway in AD. We have diminished tau pathology by inhibiting p38 MAPK signaling in cellular models, suggesting that the p38 MAPK pathway is a potent human‐derived target to combat tau pathology. PNY and SSK are co‐first‐authors. RT, WH, and DYK jointly supervised this project.