Alzheimer’s disease (AD) is a progressive neurodegenerative disorder affecting nearly 45 million people worldwide. Current therapeutic options, including cholinesterase inhibitors (rivastigmine, donepezil, and galantamine) and the NMDA receptor antagonist memantine, offer only symptomatic relief without halting disease progression. Thus, there is an urgent need to identify novel therapeutics capable of targeting the molecular drivers of AD pathology.

The hallmark features of AD—amyloid plaques and neurofibrillary tangles (NFTs)—are closely linked to tau hyperphosphorylation mediated by glycogen synthase kinase-3β (GSK-3β) and cyclin-dependent kinases (CDKs). Hyperactive GSK-3β promotes NFT formation, oxidative stress, and neuronal death.

In this study, we evaluated Indirubin-3′-oxime, a potent GSK-3β inhibitor with antioxidant properties, in a streptozotocin-induced rat model of AD. Indirubin-3′-oxime treatment (10 mg/kg, i.p.) administered for 21 days significantly improved cognitive performance in the Morris water maze and novel object recognition tests compared to untreated AD rats (p < 0.01). Biochemical assays revealed a 40–50% reduction in phosphorylated tau levels and marked inhibition of GSK-3β and CDK5 activities. Oxidative stress markers such as MDA and nitrite were significantly decreased, while antioxidant enzymes (SOD, catalase) were restored toward normal values.

Histopathological analysis showed reduced neuronal degeneration in the hippocampal CA1 region, confirming neuroprotection. These findings demonstrate that Indirubin-3′-oxime mitigates tau hyperphosphorylation and oxidative stress, thereby improving cognitive function. The results support its therapeutic potential as a disease-modifying agent in Alzheimer’s disease.