مقالات پذیرفته شده در نهمین کنگره بین المللی زیست پزشکی
Correcting Excitotoxicity in Alzheimer's Disease: The Role of Exercise in Normalizing the D-serine/NMDAR Signaling Pathway
Correcting Excitotoxicity in Alzheimer's Disease: The Role of Exercise in Normalizing the D-serine/NMDAR Signaling Pathway
Hosna soori,1,*Alireza souri,2
1. Department of Biology, CT.C, Islamic Azad University 2. Department of Physical Education and Sport Sciences, Science and Research Branch, Islamic Azad University
Introduction: D-serine, a D-amino acid produced by the enzyme serine racemase (SR), is the principal endogenous co-agonist for the N-methyl-D-aspartate receptor (NMDAR), a receptor complex that plays a key role in synaptic plasticity, learning, and memory. Healthy cognitive function is thus dependent on the integrity of D-serine/NMDAR signaling. An increasing body of evidence implicates the dysregulation of this pathway in the pathophysiology of Alzheimer’s disease (AD). Although normal aging is associated with a decline in D-serine, studies in AD models and patients suggest a paradoxical and pathological rise in D-serine in important brain areas such as the hippocampus. This overstimulation is thought to contribute to NMDAR-mediated excitotoxicity, synaptic dysfunction, and neuronal loss, which are hallmarks of AD. Consequently, strategies that can safely normalize D-serine levels represent a promising therapeutic avenue. Lifestyle interventions, particularly physical exercise, are well-established as potent modulators of brain health, promoting neurogenesis, upregulating neurotrophic factors like BDNF, and reducing neuroinflammation. However, the specific impact of exercise on the D-serine/NMDAR signaling pathway in the context of AD has not been fully elucidated. This review explores the current understanding of D-serine biology and its dysregulation in AD, and critically evaluates the evidence for exercise as a non-pharmacological strategy to positively modulate this pathway.
Methods: This is a narrative review that summarizes preclinical and clinical evidence to investigate the mechanistic link between physical exercise and the D-serine/NMDAR pathway in Alzheimer's disease. We analyzed peer-reviewed studies on D-serine's function in synaptic plasticity, its pathological dysregulation in AD, and the neurobiological effects of exercise. Findings from animal models, human observational studies, and clinical trials were integrated to evaluate the evidence for physical activity as a modulator of D-serine signaling.
Results: The literature confirms that D-serine, primarily synthesized by neuronal SR, is essential for NMDAR-dependent LTP (long-term potentiation) and memory formation. Cognitive impairment is caused by depletion of D-serine, while supplementation has been shown to enhance it in both aged rodents and older humans. In the context of AD, there is a substantial amount of evidence that points towards a pathological elevation of D-serine. Post-mortem tissue from AD patients and studies using the 3xTg-AD mouse model revealed elevated levels of D-serine in the hippocampus, which were associated with cognitive impairments. This suggests that while a basal level of D-serine is necessary for cognition, excessive levels in the context of AD pathology are detrimental.
Regarding interventions, exercise is known to exert robust neuroprotective effects, including the promotion of adult hippocampal neurogenesis, upregulation of BDNF, and attenuation of neuroinflammation. The most direct evidence linking exercise to the D-serine pathway comes from a preclinical study in 3xTg-AD mice. Memory losses were successfully rescued in three months of voluntary wheel running in this study. This behavioral recovery was directly associated with a normalization of hippocampal D-serine levels, which were pathologically high in the sedentary AD mice. The researchers also discovered that exercise restored the levels of the degrading enzyme DAO (D-amino acid oxidase), suggesting a potential mechanism for the observed reduction in D-serine. Human studies on this specific link are lacking; however, related research has shown that cognitive improvements following cognitive training are associated with increased serum D-serine, highlighting its role in neuroplasticity.
Conclusion: The D-serine/NMDAR signaling pathway is a critical regulator of synaptic health that is pathologically dysregulated in Alzheimer's disease. Preclinical evidence strongly suggests that physical exercise is a potent non-pharmacological intervention that can correct this dysregulation. The finding that voluntary running can normalize pathologically high D-serine levels and rescue memory function in an AD mouse model provides a compelling mechanistic rationale for the cognitive benefits of exercise. This also makes D-serine a possible biomarker for tracking both disease progression and the response to lifestyle interventions. Significant research gaps remain, most notably the need for human clinical trials that measure central and peripheral D-serine changes in response to structured, long-term exercise programs, using standardized methods like LC-MS/MS. Future research should aim to clarify causality in diverse AD models and explore how other factors, such as APOE4 status, may influence this pathway. Ultimately, targeting the D-serine system through exercise, potentially in combination with pharmacological strategies, represents a promising and accessible approach for the prevention and management of cognitive decline in Alzheimer's disease.