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 beta-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.

β-Amyloid (Aβ) Oligomers Impair Brain-derived Neurotrophic Factor Retrograde Trafficking by Down-regulating Ubiquitin C-terminal Hydrolase, UCH-L1

“…Consistent with the hypothesis that A␤-mediated synaptic dysfunction involves disrupted BDNF signaling, we have found that soluble A␤ impairs retrograde axonal trafficking of the BDNF receptor, TrkB (22). Retrograde axonal transport of the BDNF-TrkB complex to the soma drives downstream signaling events important for neuronal health, survival, and plasticity, including CREB-dependent gene transcription (24).…”

“…Mature BDNF-GFP was further purified by size exclusion chromatography (Amicon YM-50) where the flow-through contained the protein of interest. BDNF-GFP is indistinguishable from BDNF both biochemically and biologically (38,39), and we previously confirmed that our purified BDNF-GFP was biologically active (22). The BDNF-GFP concentration was determined by BDNF ELISA (Promega).…”

“…A␤ oligomer preparations were centrifuged (14,000 ϫ g, 10 min, 4°C); the supernatants were transferred to fresh Eppendorf tubes and stored at 4°C until use. Confirmation of A␤ oligomers was carried out by Western analysis as described previously (22).…”

Microfluidic construction of minimalistic neuronal co-cultures

“…20 The CNA circuits can be used to establish many other heterotypic co-cultures to model different neurobiological interactions, such as the neuromuscular junction, the role of glial cells during axon myelination, [46][47][48] immune cell scenarios implicated in autoimmunity-based neurodegeneration and spatially defined cues for neuronal stem cell differentiation. In addition, the compartmentalized nature of the co-culture systems enable investigations into the propagation of materials and pathological responses with notable examples being amyloid trafficking, 49 toxin dissemination, especially nanoparticulates such as manganese, and the distribution of virus and prion infectious agents. The compartmentalised systems also provide a spatially standardized imaging display for network integrity measurements and functional assays employing fluorescent Ca 2+ reporters.…”

The Transcription Factor XBP1 in Memory and Cognition: implications in Alzheimer’s Disease

“…Alternatively, a disruption of BDNF signaling would likely reduce or prevent XBP1-dependent amelioration of AD-like pathology (19). In vivo and in vitro studies have demonstrated that oligomeric Aβ alters BDNF expression/function by downregulating its transcripts or impairing axonal transport, with subsequent adverse effects (159)(160)(161)(162)(163)(164)(165). Oligomeric Aβ also reduces BDNF secretion by dendritic cells in humans, thereby decreasing neurotrophic supports for neurons and causing brain damage (166).…”