GSK-3 is essential in the pathogenesis of Alzheimer's disease
In: Journal of Alzheimer's Disease, Jg. 9 (2006-07-27), S. 309-317
Online
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Zugriff:
Glycogen synthase kinase-3 (GSK-3) is a pivotal molecule in the development of Alzheimer's disease (AD). GSK-3beta is involved in the formation of paired helical filament (PHF)-tau, which is an integral component of the neurofibrillary tangle (NFT) deposits that disrupt neuronal function, and a marker of neurodegeneration in AD. GSK-3beta has exactly the same oligonucleotide sequence as tau-protein kinase I (TPKI), which was first purified from the microtubule fraction of bovine brain. Initially, we discovered that GSK-3beta was involved in amyloid-beta (Abeta)-induced neuronal death in rat hippocampal cultures. In the present review, we discuss our initial in vitro results and additional investigations showing that Abeta activates GSK-3beta through impairment of phosphatidylinositol-3 (PI3)/Akt signaling; that Abeta-activated GSK-3beta induces hyperphosphorylation of tau, NFT formation, neuronal death, and synaptic loss (all found in the AD brain); that GSK-3beta can induce memory deficits in vivo; and that inhibition of GSK-3alpha (an isoform of GSK-3beta) reduces Abeta production. These combined results strongly suggest that GSK-3 activation is a critical step in brain aging and the cascade of detrimental events in AD, preceding both the NFT and neuronal death pathways. Therefore, therapeutics targeted to inhibiting GSK-3 may be beneficial in the treatment of this devastating disease.
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GSK-3 is essential in the pathogenesis of Alzheimer's disease
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Autor/in / Beteiligte Person: | Takashima, Akihiko |
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Zeitschrift: | Journal of Alzheimer's Disease, Jg. 9 (2006-07-27), S. 309-317 |
Veröffentlichung: | IOS Press, 2006 |
Medientyp: | unknown |
ISSN: | 1875-8908 (print) ; 1387-2877 (print) |
DOI: | 10.3233/jad-2006-9s335 |
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