Exercise Reprograms the Spatial Function of Phosphoglycerate Dehydrogenase of a Pathogenic Nuclear Transcription Factor (PHGDH): A Narrative Review

<b>Background:</b> Alzheimer's disease (AD) represents a significant therapeutic challenge, largely attributed to the complex interplay of genetic and non-genetic mechanisms. Among the latter, metabolic dysregulation has emerged as a critical factor influencing disease progression. This study proposes a paradigm shift in our understanding of the role of phosphoglycerate dehydrogenase (PHGDH), a key metabolic enzyme, which, under pathological conditions associated with AD, transitions from a protective role to a pathogenic influence through alterations in its cellular localization and function. <b>Methods:</b> To elucidate the impact of exercise on PHGDH dynamics, a narrative review methodology was employed. We conducted comprehensive searches across bibliographic databases, including PubMed, Scopus, and Web of Science, focusing on peer-reviewed articles that detail the relationship between exercise, PHGDH activity, and AD-related neuroinflammation. The review was structured around specific inclusion criteria, which prioritized studies elucidating the mechanisms underlying PHGDH's dual role in AD pathology and the influence of exercise on this process. <b>Results:</b> Our findings reveal that under AD-associated stress, PHGDH translocates to the nucleus, facilitating the activation of pro-inflammatory genes such as IKKα and HMGB1, while simultaneously suppressing autophagy and enhancing amyloid beta (Aβ) deposition. However, exercise induces the release of the myokine irisin, which inhibits PHGDH nuclear translocation through AMPK/PGC-1α signaling pathways. Additionally, peripheral effects of exercise are observed in hepatic Kupffer cells, where exercise attenuates PHGDH activity, leading to reduced systemic IL-1β release and neuroinflammation. <b>Conclusions:</b> This study underscores the potential of exercise as a precision intervention in AD management, highlighting its capacity to modulate PHGDH activity and mitigate neuroinflammatory processes. The therapeutic implications of these findings are profound, paving the way for novel diagnostic tools, such as PET probes for assessing PHGDH compartmentalization, and promoting a synergistic approach to "exercise-pharmacotherapy" in the treatment of Alzheimer's disease. Future research should aim to further delineate the mechanisms by which exercise influences metabolic pathways in the context of neurodegeneration.