Four million Americans currently suffer from Alzheimer's disease (AD), and experts estimate that 22 million people around the world will be so afflicted by 2025. Acetylcholinestase inhibitors dominate the current AD market driving its value to over $1.2 billion in 2001. In February 2002, Ebixa became the first NMDA antagonist to be approved for use in Europe. This molecule has been approved for use in patients with severe disease and will increase the market still further. However, current AD treatments center on treating symptoms and cannot modify the course of the disease. The most widely accepted hypothesis on the etiopathogenesis of AD proposes that aggregates of the amyloid protein, Aß trigger tau hyperphosphorylation and neural degeneration. Neurotoxicity is thought to be due to altered calcium regulation, mitochondrial damage and/or immune stimulation. Disease modifying products such as those able to prevent the accumulation or the toxicity of Aß42 or tau will undoubtedly provide a massive boost to the AD market. LeadDiscovery has recently produced an analysis of the therapeutic applications of glycogen synthase kinase (GSK)-3 (click here for details), an enzyme which is also selected as “Target of the Month” due to its potential role in AD. This tonically active kinase is elevated in AD brain phosphorylating tau and also possibly providing a common docking site for tau and presenelin-1, a third protein associated with AD. On the other hand, GSK-3 inhibition prevents tau hyperphosphorylation, reduces the release of Aß from transfected COS7 cells and also protects cultured neurons from cell death triggered by Aß. Finally, in addition to directly modifying the phosphorylation state of AD proteins, GSK-3 has been shown to promote neuronal apoptosis while its inhibition prevents neural cell death. These data suggest that GSK-3 inhibitors may alter both the stimuli of cell death in AD and the cell death process itself, thus supporting the development of such molecules for the treatment of AD. Despite its association with serious adverse effects, the GSK-3 inhibitor lithium has been in general use for many years as a treatment for bipolar disease. The implementation of clinical trials to determine the therapeutic activity of lithium in Alzheimer's disease is now eagerly awaited. Moreover, screening of chemical libraries for novel, more potent and specific chemical inhibitors of GSK-3 in cultured neuronal cells may provide new neuroprotective drugs of greater efficacy and less side effects than lithium.

Entry date October, 2002

Adapted from Alvarez et al, Bipolar Disord 2002 Jun;4(3):153-65 - Interested in collaborating with this group? Contact LeadDiscovery or the authors direct.

Interested in collaborating with this group? Contact leaddiscovery@bioportfolio.co.uk