Neuronal Aβ42 is enriched in small vesicles at the presynaptic side of synapses

Yu, Yang; Jans, Daniel C.; Winblad, Bengt; Tjernberg, Lars O.; Schedin‐Weiss, Sophia

doi:10.26508/lsa.201800028

Cited by 50 publications

(52 citation statements)

References 38 publications

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“…Another explanation could be that axonal boutons are upregulated due to dendritic spine instability, but over compensation by the axons results in TB loss. Or, as a recent study has shown, Aβ is enriched only at the pre-and not at the post-synapse (Yu et al, 2018), which may also explain why, in our study, axonal boutons are more affected than dendritic spines. In addition, there could be underlying sex differences in these models of AD, which has not been extensively reported.…”

Section: Discussionsupporting

confidence: 49%

Imbalance in the response of pre- and post-synaptic components to amyloidopathy

Jackson

Stephen

Tamagnini

et al. 2019

Preprint

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Alzheimer's disease (AD)-associated synaptic dysfunction drives the progression of pathology from its earliest stages. Aβ species, both soluble and in plaque deposits, have been causally related to the progressive, structural and functional impairments observed in AD. It is, however, still unclear how Aβ plaques develop over time and how they progressively affect local synapse density and turnover. Here we observed, in a mouse model of AD, that Aβ plaques grow faster in the earlier stages of the disease and if their initial area is > 500 µm 2 ; this may be due to deposition occurring in the diffuse part of the plaque. In addition, synaptic turnover is higher in the presence of amyloid pathology and this is paralleled by a reduction in pre-but not post-synaptic densities. Plaque proximity does not appear to have an impact on synaptic dynamics. These observations indicate an imbalance in the response of the pre-and post-synaptic terminals and that therapeutics, alongside targeting the underlying pathology, need to address changes in synapse dynamics. KeywordsAlzheimer's disease, amyloid plaque, synapse, in vivo two-photon imaging, dendritic spine, axonal bouton DeclarationsCompeting interests -This work was conducted at Eli Lilly's research laboratories and several authors are employees of Eli Lilly.

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Section: Discussionsupporting

confidence: 49%

Imbalance in the response of pre- and post-synaptic components to amyloidopathy

Jackson

Stephen

Tamagnini

et al. 2019

Preprint

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“…The absence of HTT phosphorylation reduced presynaptic levels of APP, restored synapse number 326 and PSD length, and attenuated memory deficits in APPPS1 mice. In contrast, there was no effect of the 327 HTT S421A mutation on amyloid plaques, on different pools of Aβ oligomers, or on extracellular and 328 intracellular Aβ42 levels in brain, although the existence of a pool of vesicular presynaptic Aβ has been 329 recently reported (Yu et al, 2018). These results suggest that HTT dephosphorylation regulates synapse 330 homeostasis by modulating presynaptic APP levels rather than modulating APP-derived Aβ production.…”

Section: Htt Phosphorylation App Presynaptic Levels and Synapse Homementioning

confidence: 89%

Presynaptic APP levels and synaptic homeostasis are regulated by Akt phosphorylation of Huntingtin

Saudou

Bruyère

Abada

et al. 2020

Preprint

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18Studies have suggested that amyloid precursor protein (APP) regulates synaptic homeostasis, but the 19 evidence has not been consistent. In particular, signaling pathways controlling APP transport to the 20 synapse in axons and dendrites remain to be identified. Having previously shown that Huntingtin (HTT), 21 the scaffolding protein involved in Huntington's disease, regulates neuritic transport of APP, we used a 22 microfluidic corticocortical neuronal network-on-a-chip to examine APP transport and localization to the 23 pre-and post-synaptic compartments. We found that HTT, upon phosphorylation by the Ser/Thr kinase 24Akt, regulates APP transport in axons but not dendrites. Expression of an unphosphorylatable HTT 25 decreased axonal anterograde transport of APP, reduced presynaptic APP levels, and increased synaptic 26 density. Ablating in vivo HTT phosphorylation in APPPS1 mice, which overexpress APP, reduced 27 presynaptic APP levels, restored synapse number and improved learning and memory. The Akt-HTT 28 pathway and axonal transport of APP thus regulate APP presynaptic levels and synapse homeostasis. 29 30 31 Key words: 32Amyloid precursor protein, Huntingtin, axonal transport, dendritic transport, synapse, microfluidics, Akt 33 phosphorylation, cortex, hippocampus, APPPS1 mice 34 35 36 the polyglutamine-expanded HTT that causes Huntington's disease (HD), facilitates APP transport by 58 increasing the velocity of APP-containing vesicles (Colin et al., 2008; Her and Goldstein, 2008). HTT is 59 a large scaffold protein that interacts with various protein complexes including molecular motor proteins 60 and, regulates consequently the transport of several cargos (Saudou and Humbert, 2016). APP transport 61 into neurites is altered upon reduction of HTT levels or by the presence of polyQ expansion on HTT 62 (Colin et al., 2008; Her and Goldstein, 2008). However, these studies did not distinguished axons from 63 dendrites and did not investigate the consequences on APP levels at the synapse both in vitro and in vivo. 64Consequently, several questions remain to be addressed regarding the interplay between HTT and APP 65 and its physiological consequences. 66To answer these questions, we studied APP and HTT in a microfluidic device that reconstitutes a 67 corticocortical neuronal network with separate presynaptic, synaptic, and postsynaptic compartments, and 68 further tested our findings in APPPS1 mice, which display AD-like pathology. We find that subtle 69 4 modifications of axonal transport of APP change synaptic levels of APP and have dramatic consequences 70 on synapse function. 71 72 Results 73Developing an in vitro corticocortical network using microfluidic chambers 74One of the major impediments to assessing APP transport in axons and dendrites under physiological 75 conditions is the difficulty of recreating a mature neuronal network in a dish. Primary cultures are usually 76 randomly distributed, with multidirectional, random connections. The use of Campenot chambers or 77 microfluidic devices made it...

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“…Several studies [32,34] also provide evidence that MVBs can undergo anterograde axonal transport. A study revealed that Aβ42, a neuronal amyloid β-peptide, was absent from the postsynaptic compartments and was enriched only within MVBs in presynaptic compartments [35]. MVBs residing in synaptic boutons have been shown to be in close contact with the presynaptic membrane [36].…”

Section: Exosomes and Neuronal Communicationmentioning

confidence: 99%

Role of Exosomes in Cancer-Related Cognitive Impairment

Koh

Tan

Toh

et al. 2020

IJMS

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A decline in cognitive function following cancer treatment is one of the most commonly reported post-treatment symptoms among patients with cancer and those in remission, and include memory, processing speed, and executive function. A clear understanding of cognitive impairment as a result of cancer and its therapy can be obtained by delineating structural and functional changes using brain imaging studies and neurocognitive assessments. There is also a need to determine the underlying mechanisms and pathways that impact the brain and affect cognitive functioning in cancer survivors. Exosomes are small cell-derived vesicles formed by the inward budding of multivesicular bodies, and are released into the extracellular environment via an exocytic pathway. Growing evidence suggests that exosomes contribute to various physiological and pathological conditions, including neurological processes such as synaptic plasticity, neuronal stress response, cell-to-cell communication, and neurogenesis. In this review, we summarize the relationship between exosomes and cancer-related cognitive impairment. Unraveling exosomes' actions and effects on the microenvironment of the brain, which impacts cognitive functioning, is critical for the development of exosome-based therapeutics for cancer-related cognitive impairment.Int. J. Mol. Sci. 2020, 21, 2755 2 of 16 attention, learning, and executive function [10]. CRCI adversely affects cancer patients and survivors, causing distress and reduced quality of life, and impacts many facets of their daily lives [11]. CRCI is complicated by many factors including the direct effects of cancer, genetic predisposition (e.g., carrier of apolipoprotein E type epsilon 4 allele [12] and brain-derived neurotrophic factor Met allele [13]), comorbidities independent of the actual disease, and/or treatments or combinations of treatments administered for the disease [14].Efforts to better understand cancer-and cancer-therapy-associated cognitive impairment have relied on methods ranging from cognitive functioning assessment to imaging technologies on brain structure and function (e.g., magnetic resonance imaging scan). However, these approaches may be limited to help us understand the etiology and pathophysiology of cognitive dysfunction. The emerging application of the use of liquid biopsies (e.g., plasma and cerebrospinal fluid) as a strategy for biomarker discovery to detect, assess and monitor CRCI is fast-expanding and evolving [15,16]. In published literature, studies have revealed that genetics and neurobiological and immunological mechanisms may be involved in the biogenesis and development of CRCI. Preclinical studies have also provided insights into the pathophysiological mechanisms underlying CRCI, including neurotoxicity and inflammatory factors, which were shown to be responsible for CRCI [17]. Nevertheless, the underlying mechanisms of CRCI have yet to be established. While the role of exosomes in cancer has been well-documented [18][19][20], the role of cancer exosomes and their ability ...

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Neuronal Aβ42 is enriched in small vesicles at the presynaptic side of synapses

Abstract: Super-resolution microscopy reveals that Aβ42 is mainly present at the presynaptic side of the synapse.

Cited by 50 publications

References 38 publications

Imbalance in the response of pre- and post-synaptic components to amyloidopathy

Imbalance in the response of pre- and post-synaptic components to amyloidopathy

Presynaptic APP levels and synaptic homeostasis are regulated by Akt phosphorylation of Huntingtin

Role of Exosomes in Cancer-Related Cognitive Impairment

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