Optic Nerve Degeneration and Ageing

نویسندگان

  • J. T. Walsh
  • I. Smirnov
  • A. Radjavi
  • S. Gadani
  • K. Tung
  • J. Kipnis
چکیده

Major pathological hallmarks of Alzheimer Disease are insoluble deposits of the short amyloid β-peptide (β-amyloid, Aβ), which is derived by sequential proteolytic cleavage from a large type I trans-membrane protein, the β-amyloid precursor protein (APP). APP is anterogradely transported by fast axonal transport in a distinct transport vesicle, but both the biochemical composition of such a vesicle as well as the specific kinesin motor responsible for transport is poorly defined. We showed by immunocytochemical studies on Drosophila motor neurons, fibroblasts and primary cortical mouse neurons, as well as time-lapse analysis and immunoisolations that APP is a cargo of a vesicle containing kinesin-1C, the small GTPase Rab3A and a specific subset of presynaptic protein components. Moreover, we report that APP is co-transported with the low density lipoprotein receptor related protein (LRP1) and show that coupling of kinesin to APP transport vesicles is impaired in absence of Rab3 GTPase activating proteins, p130 and p150. This suggests a common assembly of LRP1 and APP in a post-golgi vesicle that requires Rab3A GTPase activity for coupling of the kinesin-1c motor protein. Finally, we provide evidence for cleavage of APP in the analyzed transport vesicles by αsecretase activity. Together these studies elucidate the molecular mechanisms underlying APP trafficking and transport, which has important implications for understanding of the etiology of Alzheimer Disease. Author Disclosure(s): S. Kins: None. S.Brunholz: None. A. Szodorai: None. C. Pietrzik: None. S Brady: None.

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تاریخ انتشار 2012