Viral Infection Induces Alzheimer's Disease-Related Pathways and Senescence in iPSC-Derived Neuronal Models

Abstract

Structured AbstractO_ST_ABSINTRODUCTIONC_ST_ABSThe Pathogen Infection Hypothesis proposes that {beta}-Amyloid (A{beta}) functions as an antimicrobial peptide, with pathogen-induced aggregation potentially contributing to Alzheimers disease (AD) pathology. METHODSWe used human iPSC-derived 2D neurons and 3D cerebral organoids from wild-type and familial AD (PSEN1/2 mutant) lines to model acute infections with HSV-1 and TBEV and A{beta} aggregation. Transcriptomic and proteomic analyses were conducted to assess molecular responses. RESULTSHSV-1, but not TBEV, induced robust A{beta} clustering, which was, however, dependent on extracellular amyloid peptides. Transcriptomic profiling revealed widespread HSV-1-induced changes, including activation of neurodegeneration-related pathways. Proteomic profiling confirmed enrichment of neurodegeneration- and senescence-associated secretome signatures. PSEN1/2 mutations did not alter the acute infection response. Reanalysis of independent datasets confirmed our findings and revealed a limited protective effect of acyclovir. DISCUSSIONResults directly support the Pathogen Infection Hypothesis and suggest that preventing viral infections via vaccinations may represent a feasible approach to reducing AD risk.