Integrative pathway analysis across humans and 3D cellular models identifies the p38 MAPK-MK2 axis as a therapeutic target for Alzheimer's disease.

Alzheimer's disease (AD) presents a complex pathological landscape, posing challenges to current therapeutic strategies that primarily target amyloid-β (Aβ). Using a novel integrative pathway activity analysis (IPAA), we identified 83 dysregulated pathways common between both post-mortem AD brains and three-dimensional AD cellular models showing robust Aβ42 accumulation. p38 mitogen-activated protein kinase (MAPK) was the most upregulated common pathway. Active p38 MAPK levels increased in the cellular models, human brains, and 5XFAD mice and selectively localized to presynaptic dystrophic neurites. Unbiased phosphoproteomics confirmed increased phosphorylation of p38 MAPK substrates. Downstream activation of MAPK-activated protein kinase 2 (MK2) plays a crucial role in Aβ42-p38 MAPK-mediated tau pathology. Therapeutic targeting of the p38 MAPK-MK2 axis with selective inhibitors significantly reduced Aβ42-driven tau pathology and neuronal loss. IPAA prioritizes the best models to derisk target-drug discovery by integrating human tissue gene expression with functional readouts from cellular models, enabling the identification and validation of high-confidence AD therapeutic targets. • IPAA defines best matching functions between cellular models and human gene expression • 83 target pathways, including p38 MAPK, dysregulated in both human brains and models • Therapeutic targeting of the p38 MAPK-MK2 axis reduced AD pathology in human neurons • IPAA derisks preclinical target-drug discovery for neurodegenerative diseases Naderi and Kwak et al. developed IPAA, an integrated cellular/bioinformatics platform. IPAA derisks drug discovery by integrating Alzheimer's brain gene expression with cellular model functional readouts. By identifying and drugging the p38 MAPK-MK2 axis as a therapeutic target, and so reducing human neuronal pathology, IPAA is validated for drug discovery. [ABSTRACT FROM AUTHOR]