• Researchers employ APOE3/APOE4 heterozygous 3D human brain tissue model to mimic the effects of traumatic brain injuries (TBIs) in combination with the common latent herpes simplex virus type 1 (HSV-1) infection.
• Repetitive mild brain injuries reactivate latent HSV-1, triggering Alzheimer’s disease (AD)-like pathologies such as amyloid β plaques, tau protein phosphorylation, and gliosis, especially in younger tissues.
• This mechanism highlights the potential long-term risks of contact sports and other activities prone to repetitive head trauma, particularly for younger individuals.
• Anti-inflammatory strategies targeting IL-1β successfully reduce the damage, offering possibilities for therapeutic interventions to mitigate long-term risks.

Traumatic brain injuries (TBIs)—caused by falls, contact sports, or accidents—are a major driver of neurodegenerative diseases, including chronic traumatic encephalopathy (CTE) and AD. In a new study published in Science Signaling, researchers from Tufts University and the University of Oxford employed a previously established APOE4-carrying 3D human brain tissue model to explore how repetitive brain injuries might exacerbate the risk of neurodegeneration through the reactivation of latent HSV-1. This virus is known to infect the majority of people by the age of 60 and has been linked to AD in individuals carrying the APOE4 allele ^[1].

To simulate TBIs, Cairns et al. (2025) used devices that inflicted controlled cortical impacts and closed head injuries on the 3D brain models. Thus, the study uncovers a mechanism through which even mild repetitive TBIs can reactivate latent HSV-1. This activation leads to a cascade of detrimental events, including the accumulation of amyloid β plaques and phosphorylation of tau proteins (hallmarks of AD), and pronounced gliosis. These effects were more pronounced with repeated injuries compared with a single incident, highlighting the cumulative nature of head trauma. Notably, younger 3D brain models subjected to closed head injuries showed stronger AD-like responses than older, more mature tissue. This aligns with the high prevalence of CTE observed in professional athletes such as boxers and football players, who often begin enduring head trauma at a young age ^[2,3].

One promising aspect of the study lead by David Kaplan and Ruth Itzhaki is the successful mitigation of damage through anti-inflammatory therapies. By blocking the cytokine IL-1β, which showed increased expression upon TBI, the researchers were able to reduce HSV-1 reactivation and its downstream effects in monolayer-cultured human induced neuronal stem cells (hiNSCs). This suggests that targeted treatments immediately following head trauma could potentially prevent the development of long-term neurodegenerative conditions.

The findings by Cairns et al. mark a significant step forward in understanding the intricate relationship between traumatic brain injuries and neurodegeneration. The authors conclude that TBI-induced reactivation of latent HSV-1 is a key contributor to the development of diseases such as AD, particularly in APOE4 carriers. Additionally, they suggest that antiviral and anti-inflammatory treatments could play a critical role in reducing the burden of neurodegenerative diseases linked to (repetitive) trauma.

This article refers to:

Cairns DM, Smiley BM, Smiley JA, Khorsandian Y, Kelly M, Itzhaki RF, Kaplan DL (2025) Repetitive injury induces phenotypes associated with Alzheimer’s disease by reactivating HSV-1 in a human brain tissue model. Sci Signal 18:eado6430. DOI: 10.1126/scisignal.ado6430

Further references:

[1] Itzhaki RF, Lin WR, Shang D, Wilcock GK, Faragher B, Jamieson GA (1997) Herpes simplex virus type 1 in brain and risk of Alzheimer’s disease. Lancet 349:241–244. DOI: 10.1016/S0140-6736(96)10149-5

[2] McCrory P, Zazryn T, Cameron P (2007) The evidence for chronic traumatic encephalopathy in boxing. Sports Med 37:467–476. DOI: 10.2165/00007256-200737060-00001

[3] Daneshvar DH, Nair ES, Baucom ZH, Rasch A, Abdolmohammadi B, Uretsky M, Saltiel N, Shah A, Jarnagin J, Baugh CM, Martin BM, Palmisano JN, Cherry JD, Alvarez VE, Huber BR, Weuve J, Nowinski CJ, Cantu RC, Zafonte RD, Dwyer B, Crary JF, Goldstein LE, Kowall NW, Katz DI, Stern RA, Tripodis Y, Stein TD, McClean MD, Alosco ML, McKee AC, Mez J (2023) Leveraging football accelerometer data to quantify associations between repetitive head impacts and chronic traumatic encephalopathy in males. Nat Commun 14:3470. DOI: 10.1038/s41467-023-39183-0