# Platelet hyperreactivity and frailty in a mouse model of Alzheimer’s disease are prevented by anti-oxidant treatment

## TL;DR

This study shows that antioxidant treatment can reduce platelet hyperreactivity and prevent frailty in a mouse model of Alzheimer's disease.

## Contribution

The study identifies a novel link between platelet hyperreactivity and frailty in Alzheimer’s disease, and shows that antioxidant treatment can mitigate both.

## Key findings

- APP23 mice showed significantly more frailty than wild-type mice as they aged.
- Platelet hyperreactivity and increased pro-inflammatory functions were observed in aged APP23 mice.
- Antioxidant treatment with Tempol reduced platelet hyperreactivity and improved frailty scores in APP23 mice.

## Abstract

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.

The online version contains supplementary material available at 10.1007/s11357-025-01710-w.