Exercise-induced GPLD1 is associated with neuroprotection and improvement of hippocampal dysfunction in an Alzheimer's disease model.

UNLABELLED: This study investigated the therapeutic potential of exercise training and the associated role of Glycosylphosphatidylinositol-specific phospholipase D1 (GPLD1) in an experimental Alzheimer’s disease (AD) model. Using a D-galactose/AlCl3 induced rodent model, we evaluated behavioral impairments, AD pathological markers, and the expression of key signaling pathways linked to neurodegeneration and neuroprotection, alongside and neurotrophic factors. Male rats were divided into Control, AD, Exercise, and AD + Exercise groups. The AD model exhibited significant deficits in locomotor activity, exploratory behavior, and spatial learning/memory, alongside elevated hippocampal Aβ1–42, tau protein, AChE activity. This was accompanied by overactivation of pathways implicated in neuroinflammation and pathology (NF-κB, mTOR, GSK-3β), and downregulation of pathways crucial for neuronal survival and plasticity (Wnt3a/β-catenin, PI3K/Akt), in addition to reduced GPLD1 and BDNF. Exercise intervention significantly ameliorated these behavioral deficits, increased hippocampal BDNF, GPLD1, and restored activity in pro-survival pathways (Wnt3a/β-catenin, PI3K/Akt) while reducing AD pathology markers. Notably, the AD + Exercise group demonstrated substantial recovery in most parameters compared to the AD group. Furthermore, plasma and liver GPLD1 levels were markedly upregulated by exercise. These findings collectively suggest that exercise training is associated with robust neuroprotection, correlating with systemic GPLD1 upregulation, and highlights the GPLD1 axis for future therapeutic investigation in AD. GRAPHICAL ABSTRACT: [Image: see text]