BACE1 trafficking in neurons

Recently, we examined BACE1 trafficking by advanced live cell imaging and confocal microscopy in transfected hippocampal neurons in culture and in hippocampal slices of BACE1-YFP transgenic mice (the later studies were performed in collaboration with Dr. Robert Vassar who generated the transgenic mice). Using a series of organelle markers, we characterized dynamic localization and transport BACE1 in recycling endosomes. We discovered that BACE1 internalized from dendritic plasma membrane is exclusively trafficked towards the soma and then axonally transported in recycling endosomes by a polarized neuronal trafficking process, termed transcytosis. Moreover, we found that small GTPase Rab11 and Eps15 homology domain (EHD) family proteins regulate transcytosis of endocytosed BACE1 from somatodendritic compartment towards axons, and that this process is significant for neuronal Aβ production.

After internalization in endosomes, the Alzheimer's disease-related protein BACE1 undergoes unidirectional transport in dendrites toward the cell body although the total pool of BACE1 is able to move in both direction. BACE1 is the only protein described so far that is transported undirectionally despite the microtubules mixed polarity in dendrite.  See the full article here: A Function for EHD Family Proteins in Unidirectional Retrograde Dendritic Transport of BACE1 and Alzheimer's Disease Aβ Production - Cell Reports - 26 December 2013 (Vol. 5, Issue 6, pp. 1552-1563).

A complete presentation of this work can be found in this Prezi presentation by Virginie at the SFN 2013 nanosymposium.

We are further characterizing BACE1 transcytosis by advanced live-cell imaging strategies. We are also we are examining the molecular mechanisms of BACE1 trafficking and transport in neurons, with a focus on EHD family proteins, Rab11, and other adaptors.