Axonal BACE1 dynamics and targeting in hippocampal neurons: a role for Rab11 GTPase

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.

Prion Disease Induces Alzheimer Disease—Like Neuropathologic Changes

“…APOE-4 binds tightly to Aβ42 to clear it from neurons (30). As a result, soluble oligomeric Aβ levels are increased by APOE-4 (31). We found that concomitant changes of PrionD and AD occurred in patients who were between the ages of 50 and 85, the time when the APOE-4, a known risk factor for AD (32, 33), and neprilysin-α (34), the predominant degrading enzyme of Aβ40 and Aβ42 (35), exert their maximal effects on the development of AD (36).…”

Physiological Functions of the β-Site Amyloid Precursor Protein Cleaving Enzyme 1 and 2

“…et al, 2012), RTN3 (Deng et al, 2013), Rab11 and Eps15 homology domain proteins (Buggia-Prevot et al, 2013, 2014; Udayar et al, 2013). The enhanced localization of BACE1 at synaptic sites is suggested to increase release of Aβ by the synaptic terminals and directly facilitates amyloid deposition in AD patients (Sadleir et al, 2016).…”

Inhibiting BACE1 to reverse synaptic dysfunctions in Alzheimer’s disease

“…Depletion of both GGA1 and GGA3 induces a rapid and robust elevation of BACE1, and such an effect will likely be interfered with by flotillin, which can compete with GGA proteins for binding to the same dileucine motif in the BACE1 tail (John et al, 2014). In neurons, BACE1 is targeted to both axons and dendrites, and its preferential transport to the axonal terminus versus somatodendrites can be regulated by altered levels of calsyntenin-1 (Steuble et al, 2012; Vagnoni et al, 2012), retromer vps35 (Wang et al, 2012a; Wen et al, 2011), RTN3 (Deng et al, 2013), Rab11, and Eps15 homology domain proteins (Buggia-Prevot et al, 2014; Buggia-Prevot et al, 2013; Udayar et al, 2013). The localization of BACE1 in synaptic sites can impact the processing of its substrates.…”