Differential Genotypic Effects of HSV-1 Infection on Cognitive Function and Pathology in the 5xFAD Mouse Model
- 1Carlson College of Veterinary Medicine, Oregon State University, Corvallis, OR 97331, USA
- 2University of Veterinary Medicine Hannover, 30559 Hannover, Germany
- 3Linus Pauling Institute, Oregon State University, Corvallis, OR 97331, USA
Abstract
Alzheimer’s disease (AD) involves several different etiopathogenic mechanisms. A recent infectious theory proposes that pathogens, such as HSV-1, could be the root cause of AD. In this study, we tested this infectious theory in an HSV-1 mouse model using heterozygous 5XFAD mice (Het) carrying 5 AD-linked mutations on a C57BL/6 background and wild-type littermates (WT). We hypothesized that HSV-1 could persist in the latently infected brain and that multiple heat stresses could cause greater HSV-1 persistence, cognitive decline and AD-like pathology. Infected (HSV+) mice and non-infected (HSV-) mice with (HS) or without (NHS) heat stress at 30 and 60 dpi were examined 3 days post-heat stress for each genotype. Impairments in long-term learning were observed in infected mice after 30 dpi, regardless of genotype or heat stress. Heat stress alone impaired memory at 30 dpi across genotypes and cognitive flexibility at 60 dpi in Het mice, but this appeared to be due to the recency of the stress. When another cohort of mice with or without 1–3 heat stresses at 30, 45, and 60 dpi was examined 15 days post-heat stress, long-term learning decline was observed in all latently infected mice, regardless of genotype or heat stress. There was significantly more amyloid plaque staining in the hippocampal CA1 region in Het/HSV+/NHS mice than in Het/HSV-/NHS mice. No amyloid plaque staining was observed in WT mice, regardless of HSV-1 infection or stress. Interestingly, TNF-α transcription was higher in the Het/HSV+ mice than in Het/HSV- mice in the hippocampal region. However, IL-1β transcription was found to be significantly higher in the hippocampal region in WT/HSV+ mice with or without stress than in WT/HSV-/NHS mice. There were more active astrocytes in the CA1 region of the hippocampus of WT/HSV+ mice than in WT/HSV- mice. Active astrocyte staining did not differ significantly between infected and uninfected Het mice. Viral DNA was detected in the brains of recovered Het or WT mice at 90 dpi. HSV-1 reactivation from latency was observed in 50–75% of the explants of the cerebrum and cerebellum at 33 dpi. Therefore, a combination of amyloid plaque accumulation, neuroinflammation and viral persistence may underlie the cognitive declines observed in infected Het and WT mice.
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BibTeX
@article{lin2026differential,
title = {{Differential Genotypic Effects of HSV-1 Infection on Cognitive Function and Pathology in the 5xFAD Mouse Model}},
author = {Kerry Lin and Emily Gu and Sydney Ackerman and Xisheng Wang and Amelie F. Huener and Ibrahim Abou-Seada and Alison Li and Kathy R. Magnusson and Ling Jin},
journal = {Cells},
year = {2026},
month = oct,
doi = {10.3390/cells15201841},
url = {https://www.mdpi.com/2073-4409/15/20/1841},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - Differential Genotypic Effects of HSV-1 Infection on Cognitive Function and Pathology in the 5xFAD Mouse Model
AU - Kerry Lin
AU - Emily Gu
AU - Sydney Ackerman
AU - Xisheng Wang
AU - Amelie F. Huener
AU - Ibrahim Abou-Seada
AU - Alison Li
AU - Kathy R. Magnusson
AU - Ling Jin
PY - 2026
DA - 2026/10/10
JO - Cells
DO - 10.3390/cells15201841
UR - https://www.mdpi.com/2073-4409/15/20/1841
AB - Alzheimer’s disease (AD) involves several different etiopathogenic mechanisms. A recent infectious theory proposes that pathogens, such as HSV-1, could be the root cause of AD. In this study, we tested this infectious theory in an HSV-1 mouse model using heterozygous 5XFAD mice (Het) carrying 5 AD-linked mutations on a C57BL/6 background and wild-type littermates (WT). We hypothesized that HSV-1 could persist in the latently infected brain and that multiple heat stresses could cause greater HSV-1 persistence, cognitive decline and AD-like pathology. Infected (HSV+) mice and non-infected (HSV-) mice with (HS) or without (NHS) heat stress at 30 and 60 dpi were examined 3 days post-heat stress for each genotype. Impairments in long-term learning were observed in infected mice after 30 dpi, regardless of genotype or heat stress. Heat stress alone impaired memory at 30 dpi across genotypes and cognitive flexibility at 60 dpi in Het mice, but this appeared to be due to the recency of the stress. When another cohort of mice with or without 1–3 heat stresses at 30, 45, and 60 dpi was examined 15 days post-heat stress, long-term learning decline was observed in all latently infected mice, regardless of genotype or heat stress. There was significantly more amyloid plaque staining in the hippocampal CA1 region in Het/HSV+/NHS mice than in Het/HSV-/NHS mice. No amyloid plaque staining was observed in WT mice, regardless of HSV-1 infection or stress. Interestingly, TNF-α transcription was higher in the Het/HSV+ mice than in Het/HSV- mice in the hippocampal region. However, IL-1β transcription was found to be significantly higher in the hippocampal region in WT/HSV+ mice with or without stress than in WT/HSV-/NHS mice. There were more active astrocytes in the CA1 region of the hippocampus of WT/HSV+ mice than in WT/HSV- mice. Active astrocyte staining did not differ significantly between infected and uninfected Het mice. Viral DNA was detected in the brains of recovered Het or WT mice at 90 dpi. HSV-1 reactivation from latency was observed in 50–75% of the explants of the cerebrum and cerebellum at 33 dpi. Therefore, a combination of amyloid plaque accumulation, neuroinflammation and viral persistence may underlie the cognitive declines observed in infected Het and WT mice.
SN - 2073-4409
ER -