title: β-Amyloid (Aβ) oligomers impair brain-derived neurotrophic factor retrograde trafficking by down-regulating ubiquitin C-terminal hydrolase, UCH-L1.
abstract: We previously found that BDNF-dependent retrograde trafficking is impaired in AD transgenic mouse neurons. Utilizing a novel microfluidic culture chamber, we demonstrate that Aβ oligomers compromise BDNF-mediated retrograde transport by impairing endosomal vesicle velocities, resulting in impaired downstream signaling driven by BDNF/TrkB, including ERK5 activation, and CREB-dependent gene regulation. Our data suggest that a key mechanism mediating the deficit involves ubiquitin C-terminal hydrolase L1 (UCH-L1), a deubiquitinating enzyme that functions to regulate cellular ubiquitin. Aβ-induced deficits in BDNF trafficking and signaling are mimicked by LDN (an inhibitor of UCH-L1) and can be reversed by increasing cellular UCH-L1 levels, demonstrated here using a transducible TAT-UCH-L1 strategy. Finally, our data reveal that UCH-L1 mRNA levels are decreased in the hippocampi of AD brains. Taken together, our data implicate that UCH-L1 is important for regulating neurotrophin receptor sorting to signaling endosomes and supporting retrograde transport. Further, our results support the idea that in AD, Aβ may down-regulate UCH-L1 in the AD brain, which in turn impairs BDNF/TrkB-mediated retrograde signaling, compromising synaptic plasticity and neuronal survival.
authors.affiliation: Institute for Memory Impairments and Neurological Disorders, University of California, Irvine, California 92697. Electronic address: wpoon@uci.edu.
authors.forename: Wayne W
authors.initials: WW
authors.lastname: Poon
authors.affiliation: Institute for Memory Impairments and Neurological Disorders, University of California, Irvine, California 92697.
authors.forename: Anthony J
authors.initials: AJ
authors.lastname: Carlos
authors.affiliation: Institute for Memory Impairments and Neurological Disorders, University of California, Irvine, California 92697.
authors.forename: Brittany L
authors.initials: BL
authors.lastname: Aguilar
authors.affiliation: Institute for Memory Impairments and Neurological Disorders, University of California, Irvine, California 92697.
authors.forename: Nicole C
authors.initials: NC
authors.lastname: Berchtold
authors.affiliation: Institute for Memory Impairments and Neurological Disorders, University of California, Irvine, California 92697.
authors.forename: Crystal K
authors.initials: CK
authors.lastname: Kawano
authors.affiliation: Institute for Memory Impairments and Neurological Disorders, University of California, Irvine, California 92697.
authors.forename: Vahe
authors.initials: V
authors.lastname: Zograbyan
authors.affiliation: Institute for Memory Impairments and Neurological Disorders, University of California, Irvine, California 92697.
authors.forename: Tim
authors.initials: T
authors.lastname: Yaopruke
authors.affiliation: Department of Pathology and the Taub Institute, Columbia University, New York, New York 10032.
authors.forename: Michael
authors.initials: M
authors.lastname: Shelanski
authors.affiliation: Institute for Memory Impairments and Neurological Disorders, University of California, Irvine, California 92697.
authors.forename: Carl W
authors.initials: CW
authors.lastname: Cotman
mesh_terms: D000544:Alzheimer Disease / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D016229:Amyloid beta-Peptides / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D019208:Brain-Derived Neurotrophic Factor / Q000235:genetics / Q000378:metabolism*; D002470:Cell Survival / Q000235:genetics; D006624:Hippocampus / Q000378:metabolism* / Q000473:pathology; D006801:Humans; D051379:Mice; D008822:Mice, Transgenic; D009473:Neuronal Plasticity / Q000235:genetics; D009474:Neurons / Q000378:metabolism / Q000473:pathology; D021381:Protein Transport / Q000235:genetics; D051381:Rats; D020813:Receptor, trkB / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000235:genetics; D025801:Ubiquitin / Q000235:genetics / Q000378:metabolism; D043222:Ubiquitin Thiolesterase / Q000235:genetics / Q000378:metabolism*
chemical_list: D016229:Amyloid beta-Peptides; D019208:Brain-Derived Neurotrophic Factor; D020813:Receptor, trkB; D025801:Ubiquitin; D043222:Ubiquitin Thiolesterase; C489034:UCHL1 protein, rat; C496976:Uchl1 protein, mouse
keywords: Alzheimer Disease; Amyloid; BDNF; Microfluidic Device; Trafficking; Ubiquitin