. Phosphorylation of tau antagonizes apoptosis by stabilizing beta-catenin, a mechanism involved in Alzheimer's neurodegeneration. Proc Natl Acad Sci U S A. 2007 Feb 27;104(9):3591-6. PubMed.

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  1. Apoptosis accounts for only a minor proportion of neurons lost in the Alzheimer brain. In fact, most of the neurofibrillary tangle-bearing neurons undergo chronic degeneration rather than apoptosis even though they are constantly exposed to apoptotic stimuli. This suggests that a mechanism exists enabling these neurons to escape apoptosis.

    This paper demonstrates that upregulation of β-catenin during tau hyperphosphorylation plays a role in preventing the cells from undergoing apoptosis. The results provide evidence that tau hyperphosphorylation is essentially a sort of protective device to avoid phosphorylation of β-catenin, stabilizing it, and activating the Wnt signaling pathway so as to defer apoptosis, indicating that β-catenin mediates neuronal survival in Alzheimer disease (1,2).

    Glycogen synthase kinase 3β (GSK3β) is a key component of the Wnt signaling pathway, and at the same time is one of the most prominent tau kinases (3). In the presence of amyloid-β peptide, GSK3β is activated and β-catenin is phosphorylated and eventually degraded; however, the unphosphorylated β-catenin is stable and stimulates cell survival. The results of Wang and colleagues suggest that after activation of GSK3β tau phosphorylation may alter phosphorylation/activity of β-catenin through a competitive mechanism, leaving β-catenin essentially intact to be translocated into nuclei to promote cell survival.

    It is rewarding that a hypothesis we put forward almost 7 years ago, namely: “that a loss of function of the Wnt signaling pathway play a role in the progression of AD” (1,2) helps to explain why β-catenin is a key mediator in neuronal survival in Alzheimer disease.

    See also: 

    Inestrosa, N.C., Farias, G. and Colombres, M. (2006).Glycogen Synthase Kinase 3beta (GSK-3beta) A Key Signaling Enzyme: A Developmental Neurobiological Perspective. In “Glycogen Synthase Kinase (GSK-3) and Its Inhibitors” (Martinez, A., Castro, A. and Medina, M. Eds.), Chapter 2, pp. 25-43, John Wiley & Sons, Inc, Hoboken, New Jersey, USA.

    References:

    . Wnt signaling function in Alzheimer's disease. Brain Res Brain Res Rev. 2000 Aug;33(1):1-12. PubMed.

    . Activation of Wnt signaling rescues neurodegeneration and behavioral impairments induced by beta-amyloid fibrils. Mol Psychiatry. 2003 Feb;8(2):195-208. PubMed.

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