Therapeutic implications of glycogen synthase kinase-3ß in Alzheimer's disease: a novel therapeutic target.

Alzheimer's disease (AD) is an extremely popular neurodegenerative condition associated with dementia, responsible for around 70% of the cases. There are presently 50 million people living with dementia in the world, but this number is anticipated to increase to 152 million by 2050, posing a substantial socioeconomic encumbrance. Despite extensive research, the precise mechanisms that cause AD remain unidentified, and currently, no therapy is available. Numerous signalling paths related to AD neuropathology, including glycogen synthase kinase 3-ß (GSK-3ß), have been investigated as potential targets for the treatment of AD in current years.GSK-3ß is a proline-directed serine/threonine kinase that is linked to a variety of biological activities, comprising glycogen metabolism to gene transcription. GSK-3ß is also involved in the pathophysiology of sporadic as well as familial types of AD, which has led to the development of the GSK3 theory of AD. GSK-3ß is a critical performer in the pathology of AD because dysregulation of this kinase affects all the main symbols of the disease such as amyloid formation, tau phosphorylation, neurogenesis and synaptic and memory function. The current review highlights present-day knowledge of GSK-3ß-related neurobiology, focusing on its role in AD pathogenesis signalling pathways. It also explores the possibility of targeting GSK-3ß for the management of AD and offers an overview of the present research work in preclinical and clinical studies to produce GSK-3ß inhibitors.

Interventions in progressive supranuclear palsy.

Progressive supranuclear palsy (PSP) an atypical parkinsonian with a common phenotype comprising early falls, the characteristic slowing of vertical saccades and a frontal syndrome with marked apathy (Richardson's syndrome). Currently, no effective symptomatic or neuroprotective treatment is available for PSP. Current medical have a limited role in PSP. Novel experimental treatments include davunetide or tideglusib, both inhibitors of glycogen synthase kinase-3 (GSK-3) that failed to improve the clinical outcome of PSP patients in two recent studies. Future interventions aiming at tau dysfunction and passive or active immunization are ongoing or underway.

Quantitative Structure-Activity Relationship Analysis and a Combined Ligand-Based/Structure-Based Virtual Screening Study for Glycogen Synthase Kinase-3.

Glycogen synthase kinase-3 (GSK-3) is a multifunctional serine/threonine protein kinase which regulates a wide range of cellular processes, involving various signalling pathways. GSK-3ß has emerged as an important therapeutic target for diabetes and Alzheimer's disease. To identify structurally novel GSK-3ß inhibitors, we performed virtual screening by implementing a combined ligand-based/structure-based approach, which included quantitative structure-activity relationship (QSAR) analysis and docking prediction. To integrate and analyze complex data sets from multiple experimental sources, we drafted and validated a hierarchical QSAR method, which adopts a two-level structure to take data heterogeneity into account. A collection of 728 GSK-3 inhibitors with diverse structural scaffolds was obtained from published papers that used different experimental assay protocols. Support vector machines and random forests were implemented with wrapper-based feature selection algorithms to construct predictive learning models. The best models for each single group of compounds were then used to build the final hierarchical QSAR model, with an overall R(2) of 0.752 for the 141 compounds in the test set. The compounds obtained from the virtual screening experiment were tested for GSK-3ß inhibition. The bioassay results confirmed that 2 hit compounds are indeed GSK-3ß inhibitors exhibiting sub-micromolar inhibitory activity, and therefore validated our combined ligand-based/structure-based approach as effective for virtual screening experiments.