Repetitive injury induces phenotypes associated with Alzheimer’s disease by reactivating HSV-1 in a human brain tissue model

Science Signaling, Journal Year: 2025, Volume and Issue: 18(868)

Published: Jan. 7, 2025

Infection with herpes simplex virus type 1 (HSV-1) in the brains of APOE4 carriers increases risk Alzheimer’s disease (AD). We previously found that latent HSV-1 a three-dimensional vitro model -heterozygous human brain tissue was reactivated response to neuroinflammation caused by exposure other pathogens. Because traumatic injury also causes neuroinflammation, we surmised might similarly reactivate HSV-1. Here, examined effects one or more controlled blows our absence presence infection. After repeated, mild blows, latently infected tissues showed reactivation HSV-1; production and accumulation β amyloid phosphorylated tau (which promotes synaptic dysfunction neurodegeneration); activated gliosis, which is associated destructive neuroinflammation. These are collectively AD, dementia, chronic encephalopathy (CTE) were increased additional but absent mock-infected tissue. Blocking cytokine IL-1β prevented induction gliosis monolayer cultures after scratch wounding. thus propose repeated mechanical injuries brain, such as from direct head jarring motions head, resulting may contribute development AD related diseases some individuals.

Language: Английский

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Herpes Simplex Virus 1 Infection of Human Brain Organoids and Pancreatic Stem Cell-Islets Drives Transcripts Associated with Alzheimer’s Disease and Autoimmune Diseases

Published: July 16, 2024

Viral infections leading to inflammation have been implicated in several common diseases such as Alzheimer’s disease (AD) and type 1 diabetes (T1D). Of note, herpes simplex virus (HSV-1) has reported be associated with AD. We sought identify the transcriptomic changes due HSV-1 infection anti-viral drug (acyclovir, ACV) treatment of dissoci-ated cells from human cerebral organoids (dcOrgs) versus stem cell-derived pancreatic islets (sc-islets) gain potential biological insights into relevance HSV-1-induced AD T1D. observed that differentially expressed genes (DEGs) HSV-1-infected sc-islets were enriched for autoimmune diseases, most significantly T1D but also rheumatoid arthritis, psoriasis, Crohn’s disease, multiple sclerosis, whereas DEGs dcOrgs exclusively ACV did not rescue transcript expression disease-associated genes. Finally, we identified gene ontology categories across, or unique to, viral sc-islets, involved transferase complex, mitochondrial autophagy function. Collectively, this studies pro-vide insight molecular effects

Language: Английский

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Herpes Simplex Virus 1 Infection of Human Brain Organoids and Pancreatic Stem Cell-Islets Drives Organoid-Specific Transcripts Associated with Alzheimer’s Disease and Autoimmune Diseases

Cells, Journal Year: 2024, Volume and Issue: 13(23), P. 1978 - 1978

Published: Nov. 29, 2024

Viral infections leading to inflammation have been implicated in several common diseases, such as Alzheimer’s disease (AD) and type 1 diabetes (T1D). Of note, herpes simplex virus (HSV-1) has reported be associated with AD. We sought identify the transcriptomic changes due HSV-1 infection anti-viral drug (acyclovir, ACV) treatment of dissociated cells from human cerebral organoids (dcOrgs) versus stem cell-derived pancreatic islets (sc-islets) gain potential biological insights into relevance HSV-1-induced AD T1D. observed that differentially expressed genes (DEGs) HSV-1-infected sc-islets were enriched for autoimmune most significantly, T1D, but also rheumatoid arthritis, psoriasis, Crohn’s disease, multiple sclerosis, whereas DEGs dcOrgs exclusively The ACV was not effective rescuing transcript perturbations disease-associated genes. Finally, we identified gene ontology categories across, or unique to, viral sc-islets, involved transferase complex, mitochondrial, autophagy function. In addition, compared signatures infected coxsackie B (CVB) had T1D pathogenesis. Collectively, this study provides tissue-specific molecular effects

Language: Английский

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Alzheimer's disease‐associated CD83(+) microglia are linked with increased immunoglobulin G4 and human cytomegalovirus in the gut, vagal nerve, and brain

Alzheimer s & Dementia, Journal Year: 2024, Volume and Issue: unknown

Published: Dec. 19, 2024

Abstract INTRODUCTION While there may be microbial contributions to Alzheimer's disease (AD), findings have been inconclusive. We recently reported an AD‐associated CD83(+) microglia subtype associated with increased immunoglobulin G4 (IgG4) in the transverse colon (TC). METHODS used immunohistochemistry (IHC), IgG4 repertoire profiling, and brain organoid experiments explore this association. RESULTS superior frontal gyrus (SFG) are elevated human cytomegalovirus (HCMV) TC, anti‐HCMV cerebrospinal fluid, both HCMV SFG vagal nerve. This association was replicated independent AD cohort. HCMV‐infected cerebral organoids showed accelerated pathophysiological features (Aβ42 pTau‐212) neuronal death. DISCUSSION Findings indicate complex, cross‐tissue interactions between adaptive immune response persons AD. opportunity for antiviral therapy biomarker evidence of HCMV, IgG4, or microglia. Highlights Cross‐tissue interaction a subset Presence microglial gut. also presence cortex Replication key cohort subjects. infection accelerates production neuropathological features.

Language: Английский

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