Univ Lyon, Université Claude Bernard Lyon 1, INSERM U1052, CNRS UMR5286, Centre Léon Bérard, Cancer Research Center of Lyon, 69008, Lyon, France.
Department of Translational Research and Innovation, Centre Léon Bérard, 69373, Lyon, France.
Transl Psychiatry. 2023 Mar 10;13(1):86. doi: 10.1038/s41398-023-02376-8.
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.
许多研究强调了慢性退行性阿尔茨海默病与单纯疱疹病毒 1 型（HSV-1）感染之间的潜在联系。然而，使这种 HSV-1 依赖过程成为可能的分子机制仍有待理解。我们使用表达野生型淀粉样前体蛋白（APP）的神经元细胞感染 HSV-1，对疾病散发性形式的早期阶段进行了特征描述，并揭示了维持这种 HSV-1-阿尔茨海默病相互作用的分子机制。在这里，我们表明 HSV-1 诱导依赖于半胱天冬酶的 42 个氨基酸长的淀粉样肽（Aβ42）寡聚物的产生，然后在神经元细胞中积累。Aβ42 寡聚物和激活的半胱天冬酶 3（casp3A）聚集到在阿尔茨海默病神经元细胞中称为聚集物的细胞内结构中。在 HSV-1 感染期间，casp3A 在聚集物中的积累限制了细胞凋亡的执行，直到其结束，类似于发生在阿尔茨海默病神经元细胞患者中的细胞凋亡样事件。事实上，这种特定的由 HSV-1 驱动的细胞环境代表了疾病的早期阶段，维持了一种失败的细胞凋亡机制，这种机制可以解释阿尔茨海默病患者中 Aβ42 产生的慢性放大。最后，我们表明，非甾体抗炎药（NSAID）氟比洛芬与半胱天冬酶抑制剂联合使用，可大大降低 HSV-1 诱导的 Aβ42 寡聚物的产生。这为临床试验的结论提供了机制上的见解，这些临床试验表明 NSAID 在疾病早期阶段降低了阿尔茨海默病的发病率。因此，从我们的研究中，我们提出 Aβ42 寡聚物的半胱天冬酶依赖性产生以及细胞凋亡样事件代表了阿尔茨海默病早期阶段的恶性循环，导致 Aβ42 寡聚物的慢性放大，从而导致感染 HSV-1 的患者发生退行性疾病，如阿尔茨海默病。有趣的是，这个过程可以通过 NSAID 与半胱天冬酶抑制剂的联合治疗来靶向。
