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

The Pathogen Infection Hypothesis proposes that amyloid-β (Aβ) functions as an antimicrobial peptide, with pathogen-induced aggregation potentially contributing to Alzheimer’s disease (AD) pathology. We 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 Aβ aggregation. Transcriptomic and proteomic analyses were performed to assess molecular responses. HSV-1, but not TBEV, induced robust APP clustering in 2D and 3D models, dependent on extracellular Aβ levels. Transcriptomic profiling revealed widespread HSV-1-induced changes, including activation of neurodegeneration-related pathways. Proteomic profiling confirmed the 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. HSV-1 infection triggers APP aggregation, neuroinflammation, and cellular senescence in human brain models, supporting a causal role in AD pathogenesis.