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Related Experiment Videos

APP processing is regulated by cytoplasmic phosphorylation.

Ming-Sum Lee1, Shih-Chu Kao, Cynthia A Lemere

  • 1Department of Pathology, Harvard Medical School and Howard Hughes Medical Institute, 200 Longwood Ave., Boston, MA 02115, USA.

The Journal of Cell Biology
|October 15, 2003
PubMed
Summary
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Phosphorylation of amyloid precursor protein (APP) at threonine 668 (T668) promotes amyloid-beta peptide (Abeta) generation in Alzheimer's disease (AD). Inhibiting T668 phosphorylation significantly reduces Abeta production, suggesting a therapeutic target.

Area of Science:

  • Neuroscience
  • Molecular Biology
  • Biochemistry

Background:

  • Alzheimer's disease (AD) is characterized by amyloid-beta peptide (Abeta) aggregation in senile plaques.
  • Amyloid precursor protein (APP) processing is central to Abeta formation and AD pathogenesis.

Purpose of the Study:

  • To investigate the role of amyloid precursor protein (APP) phosphorylation at threonine 668 (T668) in APP metabolism and Abeta generation.
  • To determine the relationship between T668-phosphorylated APP (P-APP) and the beta-secretase enzyme BACE1 in Alzheimer's disease.

Main Methods:

  • Western blot analysis of hippocampal lysates from AD and control subjects.
  • Immunohistochemistry and colocalization studies in rat primary cortical neurons.
  • Biochemical fractionation using iodixanol gradients.

Related Experiment Videos

  • Inhibition of T668 phosphorylation via mutation or kinase inhibitors.

    • Main Results:

    • P-APP accumulates in vesicular structures in AD hippocampal neurons, colocalizing with endosome markers and BACE1.
    • Increased levels of T668-phosphorylated APP C-terminal fragments are found in AD brains.
    • BACE1-generated APP fragments are preferentially phosphorylated at T668 compared to alpha-secretase fragments.
    • Abolishing or inhibiting T668 phosphorylation significantly reduces Abeta production.

    Conclusions:

    • T668 phosphorylation of APP facilitates BACE1-mediated cleavage, thereby increasing Abeta generation.
    • T668 phosphorylation represents a potential therapeutic target for reducing Abeta production in Alzheimer's disease.