HSV-1 cellular model reveals links between aggresome formation and early step of Alzheimer's disease.
Journal
Translational psychiatry
ISSN: 2158-3188
Titre abrégé: Transl Psychiatry
Pays: United States
ID NLM: 101562664
Informations de publication
Date de publication:
10 03 2023
10 03 2023
Historique:
received:
19
01
2023
accepted:
20
02
2023
revised:
09
02
2023
entrez:
10
3
2023
pubmed:
11
3
2023
medline:
15
3
2023
Statut:
epublish
Résumé
Many studies highlight the potential link between the chronic degenerative Alzheimer's disease and the infection by the herpes simplex virus type-1 (HSV-1). However, the molecular mechanisms making possible this HSV-1-dependent process remain to be understood. Using neuronal cells expressing the wild type form of amyloid precursor protein (APP) infected by HSV-1, we characterized a representative cellular model of the early stage of the sporadic form of the disease and unraveled a molecular mechanism sustaining this HSV-1- Alzheimer's disease interplay. Here, we show that HSV-1 induces caspase-dependent production of the 42 amino-acid long amyloid peptide (Aβ42) oligomers followed by their accumulation in neuronal cells. Aβ42 oligomers and activated caspase 3 (casp3A) concentrate into intracytoplasmic structures observed in Alzheimer's disease neuronal cells called aggresomes. This casp3A accumulation in aggresomes during HSV-1 infection limits the execution of apoptosis until its term, similarly to an abortosis-like event occurring in Alzheimer's disease neuronal cells patients. Indeed, this particular HSV-1 driven cellular context, representative of early stages of the disease, sustains a failed apoptosis mechanism that could explain the chronic amplification of Aβ42 production characteristic of Alzheimer's disease patients. Finally, we show that combination of flurbiprofen, a non-steroidal anti-inflammatory drug (NSAID), with caspase inhibitor reduced drastically HSV-1-induced Aβ42 oligomers production. This provided mechanistic insights supporting the conclusion of clinical trials showing that NSAIDs reduced Alzheimer's disease incidence in early stage of the disease. Therefore, from our study we propose that caspase-dependent production of Aβ42 oligomers together with the abortosis-like event represents a vicious circle in early Alzheimer's disease stages leading to a chronic amplification of Aβ42 oligomers that contributes to the establishment of degenerative disorder like Alzheimer's disease in patients infected by HSV-1. Interestingly this process could be targeted by an association of NSAID with caspase inhibitors.
Identifiants
pubmed: 36898995
doi: 10.1038/s41398-023-02376-8
pii: 10.1038/s41398-023-02376-8
pmc: PMC10006237
doi:
Substances chimiques
Anti-Inflammatory Agents, Non-Steroidal
0
Caspases
EC 3.4.22.-
Amyloid beta-Peptides
0
Peptide Fragments
0
Types de publication
Journal Article
Review
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
86Informations de copyright
© 2023. The Author(s).
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