RTN3Regulates BACE1Axonal Transport

One of the pathological hallmarks of Alzheimer’s disease (AD) is the presence of senile plaques, in which amyloid deposits are surrounded by reactive astrocytes, activated microglia and dystrophic neurites. The amyloid deposits contain mostly aggregates of amyloid peptides (Aβ), which are excised from amyloid precursor protein (APP) by two endopeptidases:P-and y-secretase. BACE1has been established as the β-secretase for initiating the generation of Aβ. Increased β-secretase activity is linked to the enhanced generation of A(3and amyloid deposition in AD patients. Thus how BACE1activity is increased in AD patients has been the topic of intense research over the past several years. Because APP is predominantly expressed by neurons and deposition of Aβ aggregates in human brains is highly correlated with the Aβ released at axonal terminals, we focused our investigation of BACE1localization in the neuritic region in this study. Reticulon3(RTN3) is known to negatively regulate BACE1activity. In this study, we were also interested in whether and how RTN3regulates BACE1axonal trafficking. In a word, the present work was aimed to illucidate BACE1localization in primary neuron, as well as the mechism of RTN3regulate BACE1axonal transport and the effect on APP cleavageWe showed that BACE1was not only enriched in the late Golgi, trans-Golgi network and early endosomes but also in both axons and dendrites. BACE1was co-localized with the pre-synaptic vesicle marker Synaptophysin, indicating the presence of BACE1in synapses. Since the excessive release of Aβ from synapses is attributable to an increase in amyloid deposition, we further explored whether the presence of BACE1 in synapses would be regulated by reticulon3(RTN3), a protein previously identified as a negative regulator of BACE1. We found that co-expression of RTN3with BACE1in cultured neurons was sufficient to reduce co-localization of BACE1with Synaptophysin and PSD95. This reduction correlates with decreased anterograde transport of BACE1in axons in response to overexpressed RTN3. Our results in this study implicate that altered RTN3levels can impact the axonal transport of BACE1and demonstrate that reducing axonal transport of BACE1in axons is a viable strategy for decreasing BACE1in axonal terminals and the amyloid deposition.