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Vol. 18, Issue 10, 3835-3844, October 2007

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The Amyloid- Precursor Protein Is Phosphorylated via Distinct Pathways during Differentiation, Mitosis, Stress, and Degeneration

Department of Pharmacology and Physiology, University of Medicine and Dentistry of New Jersey, New Jersey Medical School, Newark, NJ 07103

Submitted July 24, 2006; Accepted July 9, 2007
Monitoring Editor: Erika Holzbaur

Phosphorylation of amyloid- precursor protein (APP) at Thr⁶⁶⁸ is a normal process linked to neurite extension and anterograde transport of vesicular cargo. By contrast, increased phosphorylation of APP is a pathological trait of Alzheimer's disease. APP is overexpressed in Down's syndrome, a condition that occasionally leads to increased APP phosphorylation, in cultured cells. Whether phosphorylation of APP in normal versus high APP conditions occurs by similar or distinct signaling pathways is not known. Here, we addressed this problem using brainstem-derived neurons (CAD cells). CAD cells that ectopically overexpress APP frequently show features of degenerating neurons. We found that, in degenerating cells, APP is hyperphosphorylated and colocalizes with early endosomes. By contrast, in normal CAD cells, phosphorylated APP (pAPP) is excluded from endosomes, and localizes to the Golgi apparatus and to transport vesicles within the neurites. Whereas the neuritic APP is phosphorylated by c-Jun NH₂-terminal kinase through a pathway that is modulated by glycogen synthase kinase 3, the endosomal pAPP in degenerated CAD cells results from activation of cyclin-dependent kinase 5. Additional signaling pathways, leading to APP phosphorylation, become active during stress and mitosis. We conclude that distinct pathways of APP phosphorylation operate in proliferating, differentiating, stressed, and degenerating neurons.

The online version of this article contains supplemental material at MBC Online (http://www.molbiolcell.org).

Address correspondence to: Zoia Muresan (muresazo{at}umdnj.edu) or Virgil Muresan (muresavi{at}umdnj.edu)

Abbreviations used: APP, amyloid- precursor protein; Cdk5, cyclin-dependent kinase 5; CTF, carboxy-terminal fragment; GFP, green fluorescent protein; GSK3, glycogen synthase kinase 3; JNK, c-Jun NH₂-terminal kinase; JIP, JNK-interacting protein; pAPP, Thr⁶⁶⁸-phosphorylated APP; YFP, yellow fluorescent protein.

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				V. Muresan, N. H. Varvel, B. T. Lamb, and Z. Muresan The Cleavage Products of Amyloid-{beta} Precursor Protein Are Sorted to Distinct Carrier Vesicles That Are Independently Transported within Neurites J. Neurosci., March 18, 2009; 29(11): 3565 - 3578. [Abstract] [Full Text] [PDF]