Radi_2025_Sci.Rep_15_40361

Aluminum exposure is linked to the development of many neurodegenerative disorders including Alzheimer's disease (AD), by disrupting molecular and cellular homeostasis in the brain. Chlorella vulgaris (CV), a green microalga, is reported to have antioxidant, anti-inflammatory, and neuroprotective properties. However, their role on Aluminum chloride (AlCl(3))-induced AD and amyloid beta (Abeta) clearance has not yet been fully elucidated. This research aimed to investigate the protective effectiveness of CV-loaded niosome (CV-LN) as a drug delivery system, in comparison to free form, against AlCl3-induced Alzheimer's-like neurodegeneration in rats with special emphasis on SIRT1/miRNA-134/GSK3beta axis. A niosomal formulation of Span 60, and cholesterol was chosen as an optimum formulation. Administration of CV or CV-LN dramatically improves the impaired oxidative markers, behavioral deficits, cholinergic and serotonergic dysfunctions, by significantly inhibiting monoamine oxidase, acetylcholinesterase activities and increasing serotonin level in brain of AlCl(3)-exposed rats. In parallel, CV or CV-LN triggers the activation of Sirtuin-1 (SIRT1) which downregulates miRNA-134, leading to increased brain-derived neurotrophic factor (BDNF) expression and improved neuronal survival and synaptic plasticity. Furthermore, CV or CV-LN decreases glycogen synthase kinase 3 beta (GSK3beta)-mediated Tau hyperphosphorylation associated with clearance of Abeta. Additionally, CV or CV-LN significantly inhibits neuroinflammation by decreasing glial fibrillary acidic protein (GFAP), and apoptosis via modulating BAX, Caspase-3 and BCL2. Histopathological evaluations also supported the above findings. CV-LN formulations exhibited greater neuroprotective efficacy in a rat model, possibly due to better brain delivery and bioavailability. Eventually, CV and particularly CV-LN may hold promise as potential therapeutic candidates for further investigation in the context of neurodegenerative disorders and AD, possibly through modulation of SIRT1/miRNA-134/GSK3beta axis.