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β-Amyloid (Aβ)Oligomers ImpairBrain-derivedNeurotrophic FactorRetrogradeTrafficking byDown-regulatingUbiquitin C-terminalHydrolase, UCH-L1 Wayne W. PoonAnthony J. CarlosBrittany L. Aguilar2013 год

β-Amyloid (Aβ) Oligomers Impair Brain-derived Neurotrophic Factor Retrograde Trafficking by Down-regulating Ubiquitin C-terminal Hydrolase, UCH-L1
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Аннотация: 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.Background: Axonal transport deficits are part of Alzheimer disease (AD) pathobiology.Results: β-Amyloid (Aβ) impairs BDNF-dependent retrograde signaling, which is rescued by increasing cellular UCH-L1 levels.Conclusion: In AD, Aβ impairs neurotrophin-mediated retrograde signaling by disrupting ubiquitin homeostasis.Significance: Elucidating the mechanism by which Aβ causes transport deficits that compromise synaptic plasticity and neuronal survival is crucial for discovering novel therapeutics to reverse cognitive deficits in AD. 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. Background: Axonal transport deficits are part of Alzheimer disease (AD) pathobiology. Results: β-Amyloid (Aβ) impairs BDNF-dependent retrograde signaling, which is rescued by increasing cellular UCH-L1 levels. Conclusion: In AD, Aβ impairs neurotrophin-mediated retrograde signaling by disrupting ubiquitin homeostasis. Significance: Elucidating the mechanism by which Aβ causes transport deficits that compromise synaptic plasticity and neuronal survival is crucial for discovering novel therapeutics to reverse cognitive deficits in AD.
Год издания: 2013
Авторы: Wayne W. Poon, Anthony J. Carlos, Brittany L. Aguilar, Nicole C. Berchtold, Crystal K. Kawano, Vahe Zograbyan, Tim Yaopruke, Michael L. Shelanski, Carl W. Cotman
Издательство: Elsevier BV
Источник: Journal of Biological Chemistry
Ключевые слова: Cellular transport and secretion, Nerve injury and regeneration, Alzheimer's disease research and treatments
Другие ссылки: Journal of Biological Chemistry (PDF)
Journal of Biological Chemistry (HTML)
Europe PMC (PubMed Central) (PDF)
Europe PMC (PubMed Central) (HTML)
PubMed Central (HTML)
PubMed (HTML)