02133nas a2200205   4500000000100000008004100001260001500042100001900057700002100076700002100097700002400118700001800142700002000160700002000180245013100200856005800331300001300389490000700402520151800409       2025                            d  c2025-01-071 aDana M. Cairns1 aBrooke M. Smiley1 aJordan A. Smiley1 aYasaman Khorsandian1 aMarilyn Kelly1 aRuth F. Itzhaki1 aDavid L. Kaplan00aRepetitive injury induces phenotypes associated with Alzheimer’s disease by reactivating HSV-1 in a human brain tissue model  uhttps://www.science.org/doi/10.1126/scisignal.ado6430  aeado64300 v183 aInfection with herpes simplex virus type 1 (HSV-1) in the brains of APOE4 carriers increases the risk of Alzheimer’s disease (AD). We previously found that latent HSV-1 in a three-dimensional in vitro model of APOE4-heterozygous human brain tissue was reactivated in response to neuroinflammation caused by exposure to other pathogens. Because traumatic brain injury also causes neuroinflammation, we surmised that brain injury might similarly reactivate latent HSV-1. Here, we examined the effects of one or more controlled blows to our human brain model in the absence or presence of latent HSV-1 infection. After repeated, mild controlled blows, latently infected tissues showed reactivation of HSV-1; the production and accumulation of β amyloid and phosphorylated tau (which promotes synaptic dysfunction and neurodegeneration); and activated gliosis, which is associated with destructive neuroinflammation. These effects are collectively associated with AD, dementia, and chronic traumatic encephalopathy (CTE) and were increased with additional injury but were absent in mock-infected tissue. Blocking the cytokine IL-1β prevented the induction of amyloid and gliosis in latently infected monolayer cultures after scratch wounding. We thus propose that after repeated mechanical injuries to the brain, such as from direct blows to the head or jarring motions of the head, the resulting reactivation of HSV-1 in the brain may contribute to the development of AD and related diseases in some individuals.