A novel PGK1 activator improves Alzheimer's disease by regulating glycolysis.

UNLABELLED: Alzheimer’s disease (AD) is a neurodegenerative disorder characterized by the pathological accumulation of amyloid-β (Aβ) plaques and neurofibrillary tangles. Decreased glucose metabolism and ATP levels are well-established early biomarkers of AD. Recent studies indicate that the activation of phosphoglycerate kinase 1 (PGK1), a critical enzyme in the glycolytic pathway, promotes glucose metabolism and ATP production, thus offering potential therapeutic benefits for AD. However, two significant gaps persist: The expression pattern of PGK1 across different brain cell types remains unclear, and the structural diversity of known PGK1 activators is limited, restricting comprehensive investigation. In this study, we show that PGK1 exhibits high expression in neurons in the brain, and that reduced PGK1 expression is evident in both AβO-induced SH-SY5Y cells and 3×Tg-AD mice. PGK1 overexpression mitigates AβO-induced damage by enhancing glycolysis. Through surface plasmon resonance and molecular dynamics simulations, we identify compound L03 (Specs ID: AT-051/43421517) as a novel PGK1 activator. Pretreatment with compound L03 protects against AβO-induced glycolytic dysfunction in SH-SY5Y cells. Furthermore, administration of compound L03 ameliorates cognitive deficits, Aβ deposition, and Tau hyperphosphorylation in 3×Tg-AD mice. Our findings highlight PGK1 as a crucial regulator of neuronal bioenergetics in AD and position compound L03 as a promising PGK1 activator for restoring glycolytic function. GRAPHICAL ABSTRACT: [Image: see text] SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s13195-026-02029-0.