title: β-Amyloid impairs axonal BDNF retrograde trafficking.
abstract: The neurotrophin, brain-derived neurotrophic factor (BDNF), is essential for synaptic function, plasticity and neuronal survival. At the axon terminal, when BDNF binds to its receptor, tropomyosin-related kinase B (TrkB), the signal is propagated along the axon to the cell body, via retrograde transport, regulating gene expression and neuronal function. Alzheimer disease (AD) is characterized by early impairments in synaptic function that may result in part from neurotrophin signaling deficits. Growing evidence suggests that soluble β-amyloid (Aβ) assemblies cause synaptic dysfunction by disrupting both neurotransmitter and neurotrophin signaling. Utilizing a novel microfluidic culture chamber, we demonstrate a BDNF retrograde signaling deficit in AD transgenic mouse neurons (Tg2576) that can be reversed by γ-secretase inhibitors. Using BDNF-GFP, we show that BDNF-mediated TrkB retrograde trafficking is impaired in Tg2576 axons. Furthermore, Aβ oligomers alone impair BDNF retrograde transport. Thus, Aβ reduces BDNF signaling by impairing axonal transport and this may underlie the synaptic dysfunction observed in AD.
authors.affiliation: Institute for Brain Aging and Dementia, University of California, Irvine, 1226 Gillespie NRF, Irvine, CA 92697, United States. wpoon@uci.edu
authors.forename: Wayne W
authors.initials: WW
authors.lastname: Poon
authors.forename: Mathew
authors.initials: M
authors.lastname: Blurton-Jones
authors.forename: Christina H
authors.initials: CH
authors.lastname: Tu
authors.forename: Leila M
authors.initials: LM
authors.lastname: Feinberg
authors.forename: Meredith A
authors.initials: MA
authors.lastname: Chabrier
authors.forename: Joe W
authors.initials: JW
authors.lastname: Harris
authors.forename: Noo Li
authors.initials: NL
authors.lastname: Jeon
authors.forename: Carl W
authors.initials: CW
authors.lastname: Cotman
mesh_terms: D000544:Alzheimer Disease / Q000188:drug therapy / Q000378:metabolism*; D053829:Amyloid Precursor Protein Secretases / Q000037:antagonists & inhibitors; D016229:Amyloid beta-Peptides / Q000378:metabolism*; D000818:Animals; D001370:Axonal Transport / Q000187:drug effects / Q000502:physiology*; D001369:Axons / Q000187:drug effects / Q000378:metabolism*; D019208:Brain-Derived Neurotrophic Factor / Q000378:metabolism*; D018929:Cell Culture Techniques; D051379:Mice; D008822:Mice, Transgenic; D044085:Microfluidics; D021381:Protein Transport; D020813:Receptor, trkB / Q000378:metabolism
chemical_list: D016229:Amyloid beta-Peptides; D019208:Brain-Derived Neurotrophic Factor; D020813:Receptor, trkB; D053829:Amyloid Precursor Protein Secretases