Display Settings:


Send to:

Choose Destination
See comment in PubMed Commons below
Nature. 2003 May 22;423(6938):435-9.

GSK-3alpha regulates production of Alzheimer's disease amyloid-beta peptides.

Author information

  • 1Department of Medicine, Division of Hematology-Oncology and Howard Hughes Medical Institute, University of Pennsylvania School of Medicine, Philadelphia, Philadelphia 19104-6148, USA.


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.

Comment in

  • Alzheimer's disease: Mental plaque removal. [Nature. 2003]
  • GSK-3α/β kinases and amyloid production in vivo. [Nature. 2011]
[PubMed - indexed for MEDLINE]
PubMed Commons home

PubMed Commons

How to join PubMed Commons

    Supplemental Content

    Full text links

    Icon for Nature Publishing Group Icon for Faculty of 1000
    Loading ...
    Write to the Help Desk