SUMMARY Abnormal accumulation of β-secretase (BACE1) in dystrophic neurites and presynaptic β-amyloid (Aβ) production contribute to Alzheimer's disease pathogenesis. Little, however, is known about BACE1 dynamic transport in neurons. We investigated BACE1 trafficking in hippocampal neurons using live-cell imaging and selective labeling. We report that transport vesicles containing internalized BACE1 in dendrites undergo exclusive retrograde transport, whereas they undergo bidirectional transport in axons. Unidirectional dendritic transport requires Eps15 homology domain-containing (EHD) 1 and 3 protein function. Furthermore, loss of EHD function compromises axonal sorting and dynamic axonal transport of BACE1. EHD1/3 colocalize with BACE1 and APP β-C-terminal fragments in hippocampal mossy fiber terminals, and their depletion in neurons significantly attenuates Aβ levels. These results represent the first demonstration of unidirectional endocytic transport of any cargo in dendrites. Moreover, they reveal a novel role for EHD proteins in neuronal BACE1 transcytosis and Aβ production, processes that are highly relevant for Alzheimer's disease.

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