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GSK-3alpha regulates production of Alzheimer's disease amyloid-beta peptides.
Nature. 2003 May 22; 423(6938):435-9.Nat

Abstract

Alzheimer's disease is associated with increased production and aggregation of amyloid-beta (Abeta) peptides. Abeta peptides are derived from the amyloid precursor protein (APP) by sequential proteolysis, catalysed by the aspartyl protease BACE, followed by presenilin-dependent gamma-secretase cleavage. Presenilin interacts with nicastrin, APH-1 and PEN-2 (ref. 6), all of which are required for gamma-secretase function. Presenilins also interact with alpha-catenin, beta-catenin and glycogen synthase kinase-3beta (GSK-3beta), but a functional role for these proteins in gamma-secretase activity has not been established. Here we show that therapeutic concentrations of lithium, a GSK-3 inhibitor, block the production of Abeta peptides by interfering with APP cleavage at the gamma-secretase step, but do not inhibit Notch processing. Importantly, lithium also blocks the accumulation of Abeta peptides in the brains of mice that overproduce APP. The target of lithium in this setting is GSK-3alpha, which is required for maximal processing of APP. Since GSK-3 also phosphorylates tau protein, the principal component of neurofibrillary tangles, inhibition of GSK-3alpha offers a new approach to reduce the formation of both amyloid plaques and neurofibrillary tangles, two pathological hallmarks of Alzheimer's disease.

Authors+Show Affiliations

Department of Medicine, Division of Hematology-Oncology and Howard Hughes Medical Institute, University of Pennsylvania School of Medicine, Philadelphia, Philadelphia 19104-6148, USA.No affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, P.H.S.

Language

eng

PubMed ID

12761548

Citation

Phiel, Christopher J., et al. "GSK-3alpha Regulates Production of Alzheimer's Disease Amyloid-beta Peptides." Nature, vol. 423, no. 6938, 2003, pp. 435-9.
Phiel CJ, Wilson CA, Lee VM, et al. GSK-3alpha regulates production of Alzheimer's disease amyloid-beta peptides. Nature. 2003;423(6938):435-9.
Phiel, C. J., Wilson, C. A., Lee, V. M., & Klein, P. S. (2003). GSK-3alpha regulates production of Alzheimer's disease amyloid-beta peptides. Nature, 423(6938), 435-9.
Phiel CJ, et al. GSK-3alpha Regulates Production of Alzheimer's Disease Amyloid-beta Peptides. Nature. 2003 May 22;423(6938):435-9. PubMed PMID: 12761548.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - GSK-3alpha regulates production of Alzheimer's disease amyloid-beta peptides. AU - Phiel,Christopher J, AU - Wilson,Christina A, AU - Lee,Virginia M-Y, AU - Klein,Peter S, PY - 2003/01/21/received PY - 2003/04/01/accepted PY - 2003/5/23/pubmed PY - 2003/6/19/medline PY - 2003/5/23/entrez SP - 435 EP - 9 JF - Nature JO - Nature VL - 423 IS - 6938 N2 - Alzheimer's disease is associated with increased production and aggregation of amyloid-beta (Abeta) peptides. Abeta peptides are derived from the amyloid precursor protein (APP) by sequential proteolysis, catalysed by the aspartyl protease BACE, followed by presenilin-dependent gamma-secretase cleavage. Presenilin interacts with nicastrin, APH-1 and PEN-2 (ref. 6), all of which are required for gamma-secretase function. Presenilins also interact with alpha-catenin, beta-catenin and glycogen synthase kinase-3beta (GSK-3beta), but a functional role for these proteins in gamma-secretase activity has not been established. Here we show that therapeutic concentrations of lithium, a GSK-3 inhibitor, block the production of Abeta peptides by interfering with APP cleavage at the gamma-secretase step, but do not inhibit Notch processing. Importantly, lithium also blocks the accumulation of Abeta peptides in the brains of mice that overproduce APP. The target of lithium in this setting is GSK-3alpha, which is required for maximal processing of APP. Since GSK-3 also phosphorylates tau protein, the principal component of neurofibrillary tangles, inhibition of GSK-3alpha offers a new approach to reduce the formation of both amyloid plaques and neurofibrillary tangles, two pathological hallmarks of Alzheimer's disease. SN - 0028-0836 UR - https://www.unboundmedicine.com/medline/citation/12761548/GSK_3alpha_regulates_production_of_Alzheimer's_disease_amyloid_beta_peptides_ L2 - https://doi.org/10.1038/nature01640 DB - PRIME DP - Unbound Medicine ER -