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Article Dans Une Revue Translational Psychiatry Année : 2023

HSV-1 cellular model reveals links between aggresome formation and early step of Alzheimer's disease

Catherine Helmer
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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 (A beta 42) oligomers followed by their accumulation in neuronal cells. A beta 42 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 A beta 42 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 A beta 42 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 A beta 42 oligomers together with the abortosis-like event represents a vicious circle in early Alzheimer's disease stages leading to a chronic amplification of A beta 42 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.
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Dates et versions

hal-04058236 , version 1 (04-04-2023)
hal-04058236 , version 2 (20-12-2023)

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Marie Alexandra Albaret, Julien Textoris, Bastien Dalzon, Jérémy Lambert, Morgane Linard, et al.. HSV-1 cellular model reveals links between aggresome formation and early step of Alzheimer's disease. Translational Psychiatry, 2023, 13 (1), pp.86. ⟨10.1038/s41398-023-02376-8⟩. ⟨hal-04058236v2⟩
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