Abstract
BackgroundBACE1 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.ResultsBy 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.ConclusionOur 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.
Highlights
β-site APP cleaving enzyme 1 (BACE1) is one of the two enzymes that cleave amyloid precursor protein to generate Alzheimer's disease (AD) beta amyloid peptides
Endogenous BACE1 is not detected along the axons (Figure 1C), localization of BACE1 in large terminals of hippocampal mossy fibers suggests that BACE1 traffics to mossy fiber terminals by axonal transport
A subset of BACE1-YFP fluorescence appeared in punctate structures, which colocalized with the presynaptic marker synaptophysin (Figure 1C)
Summary
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. 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. A transmembrane aspartyl protease, termed β-site APP cleaving enzyme 1 (BACE1), initiates Alzheimer's disease (AD) β-amyloid (Aβ) production by sequential proteolysis of amyloid precursor protein (APP) [1,2,3,4,5]. A single amino acid substitution adjacent to the BACE1 cleavage site of APP, which significantly reduces BACE1 cleavage and Aβ peptide generation in cultured cells, has been recently found to protect against disease onset as well as cognitive decline in the elderly without AD [10]
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