Viral Infection Induces Alzheimer's Disease-Related Pathways and Senescence in iPSC-Derived Neuronal Models
The Pathogen Infection Hypothesis proposes that amyloid-ß (Aß) 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 Aß 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 Aß 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. Overall design: For transcriptomic analysis, total RNA was extracted from single organoids using the Direct-zol RNA Microprep Kit (R2062, ZymoResearch) after UV inactivation and PBS washing. Biological replicates from six independent iPSC lines (WT1-3, AD1-3) were pooled per condition (non-treated=NTR, HSV-1, TBEV). Only RNA samples with RINe = 7.5 were processed for library preparation using the QuantSeq FWD 3' mRNA Library Prep Kit (Lexogen), and sequencing was performed on a NextSeq 500 system (Illumina), generating ~10 million reads per sample.