From Food Additives to Neurodegeneration: The Emerging Role of Polyphosphates in Tauopathies.

Neurodegenerative diseases are characterized by progressive molecular and biochemical dysfunctions that disrupt neuronal homeostasis, leading to impaired nervous system function. In tauopathies, a specific class of neurodegenerative disorders, tau protein aggregation and mitochondrial dysfunction are pathological processes interconnected in a self-reinforcing cycle. In fact, tau fibrils impair mitochondrial transport, bioenergetics, and quality control, while mitochondrial dysregulation causes tau post-translational modifications, detachment from neurons, and aggregation. In this context, inorganic polyphosphates located in cells are recently emerging as a possible modulator of both tau aggregation and mitochondrial dysfunction, thereby contributing to the onset and progression of tauopathies, including Alzheimer's disease. Additionally, inorganic polyphosphates are widely present in diets worldwide as food additives, suggesting a possible frightening connection between nutrition and tauopathies, especially in vulnerable individuals. Understanding these biochemical and nutritional interactions may support the development of novel therapeutic approaches and provide effective preventive strategies to mitigate the risk of neurodegeneration in aging populations. This review explores the current state of the art for in vivo and in vitro studies, exploring the role of endogenous polyphosphates in tau aggregation and mitochondrial dysfunction, including a novel focus point: how exogenous polyphosphates present in everyday processed food could potentially facilitate the onset of pathological conditions in humans.