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PMID: 14557249 Published · ppublish English Journal Article Research Support, Non-U.S. Gov't

APP processing is regulated by cytoplasmic phosphorylation.

The Journal of cell biology ·Vol. 163 ·No. 1 ·2003-10-13 ·Pages 83-95

Lee MS, Kao SC, Lemere CA, Xia W, Tseng HC, Zhou Y, Neve R, Ahlijanian MK, Tsai LH

Abstract

Amyloid-beta peptide (Abeta) aggregate in senile plaque is a key characteristic of Alzheimer's disease (AD). Here, we show that phosphorylation of amyloid precursor protein (APP) on threonine 668 (P-APP) may play a role in APP metabolism. In AD brains, P-APP accumulates in large vesicular structures in afflicted hippocampal pyramidal neurons that costain with antibodies against endosome markers and the beta-secretase, BACE1. Western blot analysis reveals increased levels of T668-phosphorylated APP COOH-terminal fragments in hippocampal lysates from many AD but not control subjects. Importantly, P-APP cofractionates with endosome markers and BACE1 in an iodixanol gradient and displays extensive colocalization with BACE1 in rat primary cortical neurons. Furthermore, APP COOH-terminal fragments generated by BACE1 are preferentially phosphorylated on T668 verses those produced by alpha-secretase. The production of Abeta is significantly reduced when phosphorylation of T668 is either abolished by mutation or inhibited by T668 kinase inhibitors. Together, these results suggest that T668 phosphorylation may facilitate the BACE1 cleavage of APP to increase Abeta generation.

MeSH Terms
Alzheimer Disease/metabolism,pathology Amyloid Precursor Protein Secretases Amyloid beta-Protein Precursor/metabolism Aspartic Acid Endopeptidases/metabolism Brain/metabolism Cytoplasm/metabolism Endopeptidases Humans Phosphorylation Phosphotransferases/metabolism Up-Regulation
Chemicals
Amyloid beta-Protein Precursor Phosphotransferases Amyloid Precursor Protein Secretases Endopeptidases Aspartic Acid Endopeptidases BACE1 protein, human
Authors & Affiliations
9 authors, click to expand affiliations / ORCID
Lee Ming-Sum
Department of Pathology, Harvard Medical School and Howard Hughes Medical Institute, 200 Longwood Ave., Boston, MA 02115, USA.
Kao Shih-Chu
Lemere Cynthia A
Xia Weiming
Tseng Huang-Chun
Zhou Ying
Neve Rachael
Ahlijanian Michael K
Tsai Li-Huei
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Article Info
Journal
The Journal of cell biology
Abbr.
J Cell Biol
ISSN
0021-9525
DOI
10.1083/jcb.200301115
Published
2003-10-13
Pages
83-95
Language
English
Region
United States
NLM ID
0375356
PMCID
PMC2173445
Subset
IM
External Links
PubMed source DOI: 10.1083/jcb.200301115 PMC Full Text View journal details
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