title: Axonal BACE1 dynamics and targeting in hippocampal neurons: a role for Rab11 GTPase.
abstract: BACKGROUND
  BACE1 is one of the two enzymes that cleave amyloid precursor protein to generate Alzheimer's disease (AD) beta amyloid peptides. It is widely believed that BACE1 initiates APP processing in endosomes, and in the brain this cleavage is known to occur during axonal transport of APP. In addition, BACE1 accumulates in dystrophic neurites surrounding brain senile plaques in individuals with AD, suggesting that abnormal accumulation of BACE1 at presynaptic terminals contributes to pathogenesis in AD. However, only limited information is available on BACE1 axonal transport and targeting.
  
  
  RESULTS
  By visualizing BACE1-YFP dynamics using live imaging, we demonstrate that BACE1 undergoes bi-directional transport in dynamic tubulo-vesicular carriers along axons in cultured hippocampal neurons and in acute hippocampal slices of transgenic mice. In addition, a subset of BACE1 is present in larger stationary structures, which are active presynaptic sites. In cultured neurons, BACE1-YFP is preferentially targeted to axons over time, consistent with predominant in vivo localization of BACE1 in presynaptic terminals. Confocal analysis and dual-color live imaging revealed a localization and dynamic transport of BACE1 along dendrites and axons in Rab11-positive recycling endosomes. Impairment of Rab11 function leads to a diminution of total and endocytosed BACE1 in axons, concomitant with an increase in the soma. Together, these results suggest that BACE1 is sorted to axons in endosomes in a Rab11-dependent manner.
  
  
  CONCLUSIONS
  Our results reveal novel information on dynamic BACE1 transport in neurons, and demonstrate that Rab11-GTPase function is critical for axonal sorting of BACE1. Thus, we suggest that BACE1 transcytosis in endosomes contributes to presynaptic BACE1 localization.
authors.forename: Virginie
authors.initials: V
authors.lastname: Buggia-Prévot
authors.forename: Celia G
authors.initials: CG
authors.lastname: Fernandez
authors.forename: Sean
authors.initials: S
authors.lastname: Riordan
authors.forename: Kulandaivelu S
authors.initials: KS
authors.lastname: Vetrivel
authors.forename: Jelita
authors.initials: J
authors.lastname: Roseman
authors.forename: Jack
authors.initials: J
authors.lastname: Waters
authors.forename: Vytautas P
authors.initials: VP
authors.lastname: Bindokas
authors.forename: Robert
authors.initials: R
authors.lastname: Vassar
authors.affiliation: Department of Neurobiology, The University of Chicago, Chicago, IL 60637, USA. gopal@uchicago.edu.
authors.forename: Gopal
authors.initials: G
authors.lastname: Thinakaran
mesh_terms: D053829:Amyloid Precursor Protein Secretases / Q000378:metabolism*; D000818:Animals; D016282:Aspartic Acid Endopeptidases / Q000378:metabolism*; D001370:Axonal Transport / Q000502:physiology*; D001369:Axons / Q000378:metabolism*; D011992:Endosomes / Q000378:metabolism; D006624:Hippocampus / Q000378:metabolism*; D007150:Immunohistochemistry; D051379:Mice; D008822:Mice, Transgenic; D018613:Microscopy, Confocal; D009474:Neurons / Q000378:metabolism; D009924:Organ Culture Techniques; D020691:rab GTP-Binding Proteins / Q000378:metabolism*; D000099193:rab11 GTP-Binding Proteins
chemical_list: D053829:Amyloid Precursor Protein Secretases; D016282:Aspartic Acid Endopeptidases; D020691:rab GTP-Binding Proteins; D000099193:rab11 GTP-Binding Proteins; C509282:Bace1 protein, mouse