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SAGE KE Bulletin Board

GSK-3beta regulation of neuronal polarity: A link to Alzheimer's disease (AD) ?

8 March 2005

Dietmar R. Thal

GSK-3beta regulation of neuronal polarity: A link to Alzheimer's disease (AD) ?

Comment on Yoshimura et al. "GSK-3beta regulates phosphorylation of CRMP-2 and neuronal polarity" Cell 120 (2005) 137-149 and Jiang et al. "Both the establishment and the maintenance of neuronal polarity require active mechanisms: Critical roles of GSK-3beta and its upstream regulators" Cell 120 (2005) 123-135

GSK-3beta is involved in the phosphorylation of tau and appears to play an important role in abnormal phosphorylation of tau-protein in AD (Liu et al., 2004). An early event in AD is the dislocation of abnormal tau-protein from the axon into the dendrites (Braak et al., 1994). Only in late stages of AD-related neuronal degeneration abnormal tau protein occurs in the endaxonal area of projection neurons (Thal et al., 2000). Since dislocation of tau from the axon into the dendrites indicates a failure of the cell in the regulation of cell polarity, GSK-3beta regulating neuronal polarity through phosphorylation of CRMP-2 (Jiang et al., 2005; Yoshimura et al., 2005) may play a crucial role in the beginning of the neuronal dysfunction in AD.

Braak E, Braak H, Mandelkow EM (1994) A sequence of cytoskeleton changes related to the formation of neurofi brillary tangles and neuropil threads. Acta Neuropathol 87:554-567.

Jiang H, Guo W, Liang X, Rao Y (2005) Both the establishment and the maintenance of neuronal polarity require active mechanisms: critical roles of GSK-3beta and its upstream regulators. Cell 120:123-135.

Liu SJ, Zhang JY, Li HL, Fang ZY, Wang Q, Deng HM, Gong CX, Grundke-Iqbal I, Iqbal K, Wang JZ (2004) Tau becomes a more favorable substrate for GSK-3 when it is prephosphorylated by PKA in rat brain. J Biol Chem 279:50078-50088.

Thal DR, Holzer M, R�b U, Waldmann G, Gunzel S, Zedlick D, Schober R (2000) Alzheimer-related tau-pathology in the perforant path target zone and in the hippocampal stratum oriens and radiatum correlates with onset and degree of dementia. Exp Neurol 1 63:98-110.

Yoshimura T, Kawano Y, Arimura N, Kawabata S, Kikuchi A, Kaibuchi K (2005) GSK-3beta regulates phosphorylation of CRMP-2 and neuronal polarity. Cell 120:137-149.


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