Repetitive injury induces phenotypes associated with Alzheimer’s disease by reactivating HSV-1 in a human brain tissue model, 2025, Dana M. Cairns

Editor’s summary
Infection with herpes simplex virus type 1 (HSV-1) is common, lifelong, and often in a latent state with periodic reactivation. It is a risk factor for neurodegenerative disease and dementia in some individuals, as are repeated head injuries like concussions. Cairns et al. found that latent HSV-1 was reactivated by repeated mechanical injury to mimic concussions in a three-dimensional human brain tissue model. This mechanism triggered the aggregation of β amyloid and other pathological features associated with neurodegenerative diseases in a manner dependent on the inflammatory cytokine IL-1β. The findings directly link two risk factors in a mechanism that may contribute to dementia-related disease.

Abstract
Infection 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.
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'Reanimated' herpes viruses lurking in the brain may link concussions and dementia

'Reanimated' herpes viruses lurking in the brain may link concussions and dementia