The cleavage products of amyloid-β precursor protein are sorted to distinct carrier vesicles that are independently transported within neurites

Virgil Muresan, Nicholas H. Varvel, Bruce T. Lamb, Zoia Muresan

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Abstract

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 neuntes, 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 neuntes 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.

Original languageEnglish (US)
Pages (from-to)3565-3578
Number of pages14
JournalJournal of Neuroscience
Volume29
Issue number11
DOIs
StatePublished - Mar 18 2009

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ASJC Scopus subject areas

  • Neuroscience(all)

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