Vismara Mauro, Trivigno Silvia Maria Grazia, Zarà Marta, Momi Stefania, Gresele Paolo, Camera Marina, Canobbio Ilaria, Guidetti Gianni Francesco, Torti Mauro
Department of Biology and Biotechnology L. Spallanzani, University of Pavia, Via Bassi 21, 27100, Pavia, Italy.
University School for Advanced Studies IUSS, Pavia, Italy.
Geroscience. 2025 Jun 3. doi: 10.1007/s11357-025-01710-w.
Frailty is an age-related syndrome commonly associated with different comorbidities, and its occurrence is particularly frequent in patients with Alzheimer's disease (AD). A persisting low-grade inflammation has been suggested to favor the onset of both AD and frailty. Besides their role in hemostasis and thrombosis, blood platelets are true inflammatory cells, and their direct contribution to the onset and progression of AD has been documented. In this work, we investigated whether platelet hyperreactivity and pro-oxidative functions are implicated in the development of frailty in a mouse model of AD, the APP23 mice. Assessment of 31 specific clinical signs of deterioration in mice at 3, 9, and 18 months of age demonstrated that the development of frailty was significantly more pronounced in the APP23 mice compared to wild-type littermates. In 18-month-old APP23 mice, a significant platelet hyperreactivity was detected as shown by a significantly stronger platelet aggregation in response to submaximal stimulation of both collagen and thrombin receptors. Moreover, the pro-inflammatory function of platelets, evaluated as circulating and agonist-induced platelet-neutrophil aggregate formation, was significantly increased in aged APP23 mice compared to wild-type littermates. Platelet hyperreactivity was partially prevented by prolonged treatment with the anti-oxidant agent Tempol, which reduced both agonist-induced aggregation and platelet-neutrophil aggregate formation. Importantly, prolonged treatment of APP23 mice with Tempol significantly reduced also the frailty index score in 18-month-old animals. These results outline the possible beneficial effect of an anti-oxidant treatment in hampering platelet hyperreactivity and preventing the onset of frailty associated to AD.
衰弱是一种与年龄相关的综合征，通常与不同的合并症相关，其在阿尔茨海默病（AD）患者中尤为常见。持续的低度炎症被认为有利于AD和衰弱的发生。除了在止血和血栓形成中的作用外，血小板是真正的炎症细胞，并且它们对AD的发生和进展的直接作用已有文献记载。在这项工作中，我们研究了血小板高反应性和促氧化功能是否与AD小鼠模型APP23小鼠的衰弱发展有关。对3、9和18月龄小鼠31种特定的恶化临床体征进行评估，结果表明，与野生型同窝小鼠相比，APP23小鼠的衰弱发展明显更显著。在18月龄的APP23小鼠中，检测到明显的血小板高反应性，表现为对胶原蛋白和凝血酶受体的亚最大刺激反应时血小板聚集明显增强。此外，与野生型同窝小鼠相比，老年APP23小鼠中作为循环和激动剂诱导的血小板-中性粒细胞聚集体形成评估的血小板促炎功能显著增加。用抗氧化剂Tempol长期治疗可部分预防血小板高反应性，这降低了激动剂诱导的聚集和血小板-中性粒细胞聚集体形成。重要 的是，用Tempol长期治疗APP23小鼠也显著降低了18月龄动物的衰弱指数评分。这些结果概述了抗氧化治疗在抑制血小板高反应性和预防与AD相关的衰弱发生方面可能的有益作用。
