Amyloid-β Oligomers May Impair SNARE-Mediated Exocytosis by Direct Binding to Syntaxin 1a

Yang, Yoosoo; Kim, Jaewook; Kim, Hye Yun; Ryoo, Nayeon; Lee, Se-Jin; Kim, Young Soo; Rhim, Hyewhon; Shin, Young Kil

doi:10.1016/j.celrep.2015.07.044

Cited by 58 publications

(52 citation statements)

References 52 publications

(66 reference statements)

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“…Given the increased amount of higher order Aβ42 oligomers in rpAD[18], it is plausible to suggest that this process occurs to a greater extent in rpAD. This hypothesis is supported by a recent study that showed that Aβ oligomers bind to syntaxin 1A, which is an example key presynaptic protein that is up-regulated in rpAD plaques, and this binding prevents synaptic vesicle release and leads to synaptic impairment[87]. …”

Section: Discussionmentioning

confidence: 75%

Proteomic differences in amyloid plaques in rapidly progressive and sporadic Alzheimer’s disease

Nayak²,

et al. 2017

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Rapidly progressive Alzheimer’s disease (rpAD) is a particularly aggressive form of Alzheimer’s disease, with a median survival time of 7–10 months after diagnosis. Why these patients have such a rapid progression of Alzheimer’s disease is currently unknown. To further understand pathological differences between rpAD and typical sporadic Alzheimer’s disease (sAD) we used localized proteomics to analyze the protein differences in amyloid plaques in rpAD and sAD. Label-free quantitative LC-MS/MS was performed on amyloid plaques microdissected from rpAD and sAD patients (n=22 for each patient group) and protein expression differences were quantified. On average, 913±30 (mean±SEM) proteins were quantified in plaques from each patient and 279 of these proteins were consistently found in plaques from every patient. We found significant differences in protein composition between rpAD and sAD plaques. We found that rpAD plaques contained significantly higher levels of neuronal proteins (p=0.0017) and significantly lower levels of astrocyte proteins (p=1.08x10−6). Unexpectedly, cumulative protein differences in rpAD plaques did not suggest accelerated typical sAD. Plaques from patients with rpAD were particularly abundant in synaptic proteins, especially those involved in synaptic vesicle release, highlighting the potential importance of synaptic dysfunction in the accelerated development of plaque pathology in rpAD. Combined, our data provides new direct evidence that amyloid plaques do not all have the same protein composition and that the proteomic differences in plaques could provide important insight into the factors that contribute to plaque development. The cumulative protein differences in rpAD plaques suggest rpAD may be a novel subtype of Alzheimer’s disease.

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Section: Discussionmentioning

confidence: 75%

Proteomic differences in amyloid plaques in rapidly progressive and sporadic Alzheimer’s disease

Nayak²,

et al. 2017

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“…Intracellular Aβ is enriched in both AD human brains and AD mouse models in association with dystrophic neurites and abnormal synaptic morphology (LaFerla et al, 2007; Spires-Jones and Hyman, 2014). Intracellular Aβ was proposed to induce presynaptic dysfunction, which might be one of the pathophysiological origins of early AD (Parodi et al, 2010; Yang et al, 2015). Several lines of evidence indicate that Aβ1-42 is associated with LEs or multivesicular bodies (MVBs) and AVs in AD brains (Takahashi et al, 2004, 2013, 2002; Yu et al, 2005).…”

Section: Introductionmentioning

confidence: 99%

Impaired retrograde transport of axonal autophagosomes contributes to autophagic stress in Alzheimer’s disease neurons

Tammineni

Feng

et al. 2017

eLife

116

102

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Neurons face unique challenges of transporting nascent autophagic vacuoles (AVs) from distal axons toward the soma, where mature lysosomes are mainly located. Autophagy defects have been linked to Alzheimer’s disease (AD). However, the mechanisms underlying altered autophagy remain unknown. Here, we demonstrate that defective retrograde transport contributes to autophagic stress in AD axons. Amphisomes predominantly accumulate at axonal terminals of mutant hAPP mice and AD patient brains. Amyloid-β (Aβ) oligomers associate with AVs in AD axons and interact with dynein motors. This interaction impairs dynein recruitment to amphisomes through competitive interruption of dynein-Snapin motor-adaptor coupling, thus immobilizing them in distal axons. Consistently, deletion of Snapin in mice causes AD-like axonal autophagic stress, whereas overexpressing Snapin in hAPP neurons reduces autophagic accumulation at presynaptic terminals by enhancing AV retrograde transport. Altogether, our study provides new mechanistic insight into AD-associated autophagic stress, thus establishing a foundation for ameliorating axonal pathology in AD.DOI: http://dx.doi.org/10.7554/eLife.21776.001

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“…An answer may be provided by a study that showed that endocytosed Aβ42 could accumulate in endosomes, increasing their membrane permeability and facilitating Aβ cytosolic accumulation and neuronal toxicity (Yang et al, 1998). Moreover, a recent study demonstrated that Aβ oligomers in vitro could inhibit the SNARE fusion complex assembly by direct binding to syntaxin-1a (Yang et al, 2015). Besides, in vitro, Aβ seems to be able to block synaptophysin complex formation with VAMP2 with relevance for SV exocytosis (Russell et al, 2012).…”

Section: Aβ-direct Impact On Synaptic Traffickingmentioning

confidence: 99%

Intracellular Trafficking Mechanisms of Synaptic Dysfunction in Alzheimer’s Disease

Perdigão

Barata

Araújo

et al. 2020

Front. Cell. Neurosci.

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Alzheimer's disease (AD) is the most common neurodegenerative disease characterized by progressive memory loss. Although AD neuropathological hallmarks are extracellular amyloid plaques and intracellular tau tangles, the best correlate of disease progression is synapse loss. What causes synapse loss has been the focus of several researchers in the AD field. Synapses become dysfunctional before plaques and tangles form. Studies based on early-onset familial AD (eFAD) models have supported that synaptic transmission is depressed by β-amyloid (Aβ) triggered mechanisms. Since eFAD is rare, affecting only 1% of patients, research has shifted to the study of the most common late-onset AD (LOAD). Intracellular trafficking has emerged as one of the pathways of LOAD genes. Few studies have assessed the impact of trafficking LOAD genes on synapse dysfunction. Since endocytic traffic is essential for synaptic function, we reviewed Aβ-dependent and independent mechanisms of the earliest synaptic dysfunction in AD. We have focused on the role of intraneuronal and secreted Aβ oligomers, highlighting the dysfunction of endocytic trafficking as an Aβ-dependent mechanism of synapse dysfunction in AD. Here, we reviewed the LOAD trafficking genes APOE4, ABCA7, BIN1, CD2AP, PICALM, EPH1A, and SORL1, for which there is a synaptic link. We conclude that in eFAD and LOAD, the earliest synaptic dysfunctions are characterized by disruptions of the presynaptic vesicle exo-and endocytosis and of postsynaptic glutamate receptor endocytosis. While in eFAD synapse dysfunction seems to be triggered by Aβ, in LOAD, there might be a direct synaptic disruption by LOAD trafficking genes. To identify promising therapeutic targets and biomarkers of the earliest synaptic dysfunction in AD, it will be necessary to join efforts in further dissecting the mechanisms used by Aβ and by LOAD genes to disrupt synapses.

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Amyloid-β Oligomers May Impair SNARE-Mediated Exocytosis by Direct Binding to Syntaxin 1a

Cited by 58 publications

References 52 publications

Proteomic differences in amyloid plaques in rapidly progressive and sporadic Alzheimer’s disease

Proteomic differences in amyloid plaques in rapidly progressive and sporadic Alzheimer’s disease

Impaired retrograde transport of axonal autophagosomes contributes to autophagic stress in Alzheimer’s disease neurons

Intracellular Trafficking Mechanisms of Synaptic Dysfunction in Alzheimer’s Disease

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