title: Increased expression of reticulon 3 in neurons leads to reduced axonal transport of β site amyloid precursor protein-cleaving enzyme 1.
abstract: BACE1 is the sole enzyme responsible for cleaving amyloid precursor protein at the β-secretase site, and this cleavage initiates the generation of β-amyloid peptide (Aβ). Because amyloid precursor protein is predominantly expressed by neurons and deposition of Aβ aggregates in the human brain is highly correlated with the Aβ released at axonal terminals, we focused our investigation of BACE1 localization on the neuritic region. We show that BACE1 was not only enriched in the late Golgi, trans-Golgi network, and early endosomes but also in both axons and dendrites. BACE1 was colocalized with the presynaptic vesicle marker synaptophysin, indicating the presence of BACE1 in synapses. Because 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 was regulated by reticulon 3 (RTN3), a protein identified previously as a negative regulator of BACE1. We found that RTN3 is not only localized in the endoplasmic reticulum but also in neuritic regions where no endoplasmic reticulum-shaping proteins are detected, implicating additional functions of RTN3 in neurons. Coexpression of RTN3 with BACE1 in cultured neurons was sufficient to reduce colocalization of BACE1 with synaptophysin. This reduction correlated with decreased anterograde transport of BACE1 in axons in response to overexpressed RTN3. Our results in this study suggest that altered RTN3 levels can impact the axonal transport of BACE1 and demonstrate that reducing axonal transport of BACE1 in axons is a viable strategy for decreasing BACE1 in axonal terminals and, perhaps, reducing amyloid deposition.
authors.affiliation: From the State Key Laboratory of Medical Genetics, Xiangya Medical School, Central South University, Changsha, Hunan 410078, China and.
authors.forename: Minzi
authors.initials: M
authors.lastname: Deng
authors.affiliation: the Department of Neurosciences, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio 44195.
authors.forename: Wanxia
authors.initials: W
authors.lastname: He
authors.affiliation: From the State Key Laboratory of Medical Genetics, Xiangya Medical School, Central South University, Changsha, Hunan 410078, China and.
authors.forename: Ya
authors.initials: Y
authors.lastname: Tan
authors.affiliation: From the State Key Laboratory of Medical Genetics, Xiangya Medical School, Central South University, Changsha, Hunan 410078, China and.
authors.forename: Hailong
authors.initials: H
authors.lastname: Han
authors.affiliation: the Department of Neurosciences, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio 44195.
authors.forename: Xiangyou
authors.initials: X
authors.lastname: Hu
authors.affiliation: From the State Key Laboratory of Medical Genetics, Xiangya Medical School, Central South University, Changsha, Hunan 410078, China and.
authors.forename: Kun
authors.initials: K
authors.lastname: Xia
authors.affiliation: From the State Key Laboratory of Medical Genetics, Xiangya Medical School, Central South University, Changsha, Hunan 410078, China and. Electronic address: zhangzhuohua@sklmg.edu.cn.
authors.forename: Zhuohua
authors.initials: Z
authors.lastname: Zhang
authors.affiliation: the Department of Neurosciences, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio 44195. Electronic address: yanr@ccf.org.
authors.forename: Riqiang
authors.initials: R
authors.lastname: Yan
mesh_terms: D000682:Amyloid / Q000235:genetics / Q000378:metabolism*; D053829:Amyloid Precursor Protein Secretases / Q000235:genetics / Q000378:metabolism*; D016564:Amyloid beta-Protein Precursor / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D016282:Aspartic Acid Endopeptidases / Q000235:genetics / Q000378:metabolism*; D001369:Axons / Q000378:metabolism; D001693:Biological Transport, Active / Q000235:genetics; D006801:Humans; D051379:Mice; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism*; D016501:Neurites / Q000378:metabolism*; D013569:Synapses / Q000378:metabolism; D021601:trans-Golgi Network / Q000235:genetics / Q000378:metabolism*
chemical_list: D000682:Amyloid; D016564:Amyloid beta-Protein Precursor; D009419:Nerve Tissue Proteins; C482720:Rtn3 protein, mouse; D053829:Amyloid Precursor Protein Secretases; D016282:Aspartic Acid Endopeptidases; C509282:Bace1 protein, mouse
keywords: Alzheimer Disease; Amyloid Precursor Protein; Axonal Transport; BACE1; Confocal Microscopy; Kymograph; RTN3; Secretases; Synapses; Synaptic Localization