β-Amyloid impairs axonal BDNF retrograde trafficking.
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.
Poon
Wayne W
WW
Institute for Brain Aging and Dementia, University of California, Irvine, 1226 Gillespie NRF, Irvine, CA 92697, United States. wpoon@uci.edu
Blurton-Jones
Mathew
M
Tu
Christina H
CH
Feinberg
Leila M
LM
Chabrier
Meredith A
MA
Harris
Joe W
JW
Jeon
Noo Li
NL
Cotman
Carl W
CW
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
D016229:Amyloid beta-Peptides; D019208:Brain-Derived Neurotrophic Factor; D020813:Receptor, trkB; D053829:Amyloid Precursor Protein Secretases