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The Journal of Neuroscience, March 18, 2009, 29(11):3565-3578; doi:10.1523/JNEUROSCI.2558-08.2009

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Cellular/Molecular
The Cleavage Products of Amyloid-β Precursor Protein Are Sorted to Distinct Carrier Vesicles That Are Independently Transported within Neurites

Virgil Muresan,¹ Nicholas H. Varvel,^2,3 Bruce T. Lamb,^2,3 and Zoia Muresan¹

¹Department of Pharmacology and Physiology, University of Medicine and Dentistry of New Jersey, New Jersey Medical School, Newark, New Jersey 07103, ²Department of Neurosciences, Lerner Research Institute, The Cleveland Clinic Foundation, Cleveland, Ohio 44195, and ³Department of Neurosciences, Case Western Reserve University, Cleveland, Ohio 44106

Correspondence should be addressed to either Zoia Muresan or Virgil Muresan, Department of Pharmacology and Physiology, University of Medicine and Dentistry of New Jersey, New Jersey Medical School, 185 South Orange Avenue, MSB, I-665/I-683, Newark, NJ 07103. Email: muresazo{at}umdnj.edu or Email: muresavi{at}umdnj.edu

The amyloid-β (Aβ) precursor protein (APP), a transmembrane protein that undergoes proteolytic cleavage into defined fragments, has been implicated in axonal transport. The proposed role of APP as a vesicle receptor for the microtubule motor kinesin-1 has relevance for the pathogenesis of Alzheimer's disease. Nevertheless, this function, which relies on the transport to the cell periphery of full-length APP rather than its cleavage fragments, remains controversial. Other proposed functions of APP, such as regulating transcription, neurogenesis, cell movement, or neurite growth also rely on APP's presence as a full-length protein at the cell surface, implying that APP cleavage occurs after its transport to the cell periphery. To test this hypothesis, we mapped the localization of various APP epitopes in neurons in culture and in the mouse brain. Surprisingly, epitopes from the N-terminal, C-terminal, and central (Aβ) domains of APP each showed a distinct distribution throughout the cell and rarely colocalized. Within neurites, these epitopes were localized to distinct transport vesicles that associated with different sets of microtubules and, occasionally, actin filaments. C-terminal APP fragments were preferentially transported into neurites as phosphorylated forms, entered the lamellipodium and filopodia of growth cones, and concentrated in regions of growth cone turning and advancement (unlike the N-terminal and Aβ fragments). We conclude that, under normal conditions, the proteolytic cleavage of APP primarily occurs before its sorting into axonal transport vesicles and the cleaved fragments segregate into separate vesicle populations that reach different destinations, and thus have different functions.

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Received June 9, 2008; revised Jan. 18, 2009; accepted Feb. 12, 2009.

Correspondence should be addressed to either Zoia Muresan or Virgil Muresan, Department of Pharmacology and Physiology, University of Medicine and Dentistry of New Jersey, New Jersey Medical School, 185 South Orange Avenue, MSB, I-665/I-683, Newark, NJ 07103. Email: muresazo{at}umdnj.edu or Email: muresavi{at}umdnj.edu

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				Z. Wang, B. Wang, L. Yang, Q. Guo, N. Aithmitti, Z. Songyang, and H. Zheng Presynaptic and Postsynaptic Interaction of the Amyloid Precursor Protein Promotes Peripheral and Central Synaptogenesis J. Neurosci., September 2, 2009; 29(35): 10788 - 10801. [Abstract] [Full Text] [PDF]

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