Li HL, Wang HH, Liu SJ, Deng YQ, Zhang YJ, Tian Q, Wang XC, Chen XQ, Yang Y, Zhang JY, Wang Q, Xu H, Liao FF, Wang JZ. 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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Catholic University of Chile
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:
De Ferrari GV, Inestrosa NC. Wnt signaling function in Alzheimer's disease. Brain Res Brain Res Rev. 2000 Aug;33(1):1-12. PubMed.
De Ferrari GV, Chacón MA, Barría MI, Garrido JL, Godoy JA, Olivares G, Reyes AE, Alvarez A, Bronfman M, Inestrosa NC. 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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