Systemic Modulators: Potential Mechanism for the 5-HT System to Mediate Exercise Amelioration in Alzheimer's Disease

As a neurodegenerative disease closely related to age-related changes, Alzheimer's disease (AD) is rapidly becoming one of the most resource-intensive and deadly diseases of this century. As a systemic neurotransmitter system with widespread distribution throughout the central and peripheral nervous systems, the 5-hydroxytryptamine (5-HT) system not only plays an important role in antidepressant therapy but also shows potential value in improving AD symptoms. The 5-HT system may facilitate the prevention and treatment of AD by impacting its pathological processes through various pathways, such as the regulation of Aβ deposition, hyperphosphorylation of Tau, central and peripheral neuroinflammation, and the interactions with the cholinergic and BDNF systems. In addition, regular exercise, as a non-pharmacological intervention, provides systemic and multi-level physical health benefits. Given the high sensitivity of the 5-HT system to exercise, this paper reviews its crucial role and potential mechanisms in alleviating AD through exercise. From perspective of the integrative biology of exercise, we propose several crosstalk mechanisms between the peripheral and central systems mediated by the 5-HT system. These mechanisms serve as a bridge for the treatment of AD and offer novel ideas and strategies for future therapeutic approaches.