Regulation of GSK 3b by beta amyloid and ApoE4

Since the mid-1990s there has been a near exponential rise in the level of glycogen synthase kinase-3 beta (GSK-3b) related research. Consequently the therapeutic potential of GSK-3b inhibitors has become a major area of pharmaceutical interest. A recent report produced by LeadDiscovery analysts under the editorial guidance of field-leader, Dr Hagit Eldar-Finkelman, offers a state of the art overview of GSK-3b analyzing the therapeutic role of inhibitors of this enzyme (click here for access). The report concludes that there is particularly strong evidence to support the development of GSK-3b inhibitors as 1) antihyperglycemic, insulin sensitizing and insulinotropin agents for use in diabetics; 2) inhibitors of neuronal apoptosis and neurological decline in stroke patients; and 3) treatments for Alzheimer's disease.

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 value of this therapeutic class to over US$1.2 billion in 2001 (click here for a full analysis of therapeutics for neurodegenerative disorders). Although current AD treatments center on treating symptoms, future strategies are more likely to modify the course of the disease. The most widely accepted hypothesis on the etiopathogenesis of AD proposes that aggregates of the Abeta form in the brain. Under normal conditions, the predominant amyloid peptide secreted is Abeta(1-40) with about 10-15% being the longer 1-42 form. Normally, the intracellular skeleton act as scaffolds, maintaining neuronal and nutrient transport. In AD, these fibers begin to twist and tangle. The neuron loses its shape and also becomes unable to transport nutrients properly; it eventually dies. The fiber tangles remain in the brain long after the dead neuron has been cleared away. These neurofibrillary tangles are thought to be formed following hyperphosphorylation of their tau protein component triggered by the longer more toxic form of Abeta.

Like Abeta, apoE has also been proposed to play a central role in the neuropathology of AD. ApoE is found in the lipid-protein complexes that move lipids around the body, and the most common isoform is apoE3. In 1993, scientists discovered that individuals with the apoE4 isoform are at risk for developing Alzheimer’s disease at an earlier age than people with apoE3 or apoE2. A number of hypotheses have been proposed to explain the isoform specific association of apoE and AD. One of them proposes that apoE isoforms may contribute differentially to neurofibrillary tangle formation, while another concept is that apoE4 is neurotoxic.

As discussed in our recent DiscoveryDossier, GSK-3b is elevated in AD brain, while GSK-3b inhibitors prevent tau hyperphosphorylation, and also protect cultured neurons from cell death triggered by Abeta. Thus the regulation of GSK-3b activity by key AD proteins such as Abeta and apoE may contribute to the eitiology of this disease. GSK 3b activity is regulated by multiple mechanisms. GSK 3b is inactivated by phosphorylation of serine 9 with several kinases having been found to mediate this event, including protein kinase B (PKB) and protein kinase C (PKC). In contrast to this inhibition, phosphorylation of tyrosine 216 increases GSK 3b activity. This has been shown to be mediated by some tyrosine kinases (ZAK1, Fyn) and also by transient increases in Ca2+. In their recent J Neurochem paper Cedazo-Minguez et al report the effect of Abeta and apoE on the regulatory mechanisms in human neuroblastoma cells.

This group found that apoE3, apoE4 and Abeta transiently decreased phosphorylation of cytosolic GSK-3b at ser 9 indicative of a transient activation, although the effects of apoE4 were considerably longer lived than those of apoE3. The effect of apoE4 was mirrored by an increase in PKB activity; that of Abeta was mirrored by an increase in PKC-alpha activity. ApoE4 and Abeta both produced a transient increase in cytosolic and nuclear phosphorylation of tyr 216, indicative of GSK 3b activation, while apoE3 had no effect. This effect was mirrored by a transient increase in intracellular calcium levels.

GSK 3b phosphorylation of b catenin targets it for degradation. In contrast, inhibition of GSK 3b activity leads to the translocation of beta catenin into the nucleus where it promotes transcription and cell survival. The net effect early reduction of ser 9 phosphorylation and increased tyr 216 phosphorylation by ApoE4 or Abeta was to increase GSK 3b activity as indicated by a decrease in nuclear beta catenin. This is reflected by data showing that both ApoE4 and Abeta rapidly increase cell death reaching a plateau at 3-5 hours.

This study is important because not only does it link the key AD proteins, Abeta and apoE4 with regulation of GSK 3b but it also helps explain the differential effects of apoE3 and apoE4 in AD. Furthermore, by clarifying the molecular mechanisms through which Abeta and apoE4 modulate GSK 3b activity, new targets are advanced which may limit the pathological effects of these proteins

Entry date Thursday, January 22, 2004

Adapted from Cedazo-Minguez et al, J Neurochem. 2003 Dec; 87(5): 1152-64.