Amyloid Beta Peptides Block New Synapse Assembly by Nogo Receptor-Mediated Inhibition of T-Type Calcium Channels

Zhao, Yongliang; Sivaji, Sivaprakash; Chiang, Michael; Ali, Haadi; Zukowski, Monica; Ali, Sareen T.; Kennedy, Bryan; Sklyar, Alex; Cheng, Ann‐Joy; Guo, Zihan; Reed, Alexander K.; Kodali, Ravindra; Borowski, Jennifer; Frost, Georgia; Beukema, Patrick; Wills, Zachary P.

doi:10.1016/j.neuron.2017.09.041

Cited by 41 publications

(29 citation statements)

References 59 publications

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“…The sizes of the aggregates in the presence of NaCl, are also larger compared to the no salt condition. The aggregate size after 5 h of incubation without salt was~60 nm 3 (Figure 3f), whereas similar sized aggregates were observed within 1 h of incubation in the presence of NaCl (Figure 3c). These results clearly indicate that the presence of NaCl strongly influences the acceleration of aggregation and becomes an important factor allowing aggregates to grow faster.…”

Section: Aggregation On Binary Slb Mixture (Popc:pops)mentioning

confidence: 83%

“…Growing evidence suggests the involvement of protein oligomers in the development of protein misfolding diseases, including Alzheimer's disease (AD) and Parkinson's disease (PD); however, limited knowledge exists regarding the molecular mechanisms behind the aggregation processes for these oligomers [1][2][3][4]. The amyloid cascade hypothesis (ACH), proposed more than a quarter-century ago [5], is the major model used to describe the pathology of AD and other neurodegenerative diseases [5][6][7][8][9].…”

Section: Introductionmentioning

confidence: 99%

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Interaction of Aβ42 with Membranes Triggers the Self-Assembly into Oligomers

Banerjee

Hashemi

Zagorski

et al. 2020

IJMS

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The self-assembly of amyloid β (Aβ) proteins into oligomers is the major pathogenic event leading to Alzheimer’s disease (AD). Typical in vitro experiments require high protein concentrations, whereas the physiological concentration of Aβ is in the picomolar to low nanomolar range. This complicates the translation of results obtained in vitro to understanding the aggregation process in vivo. Here, we demonstrate that Aβ42 self-assembles into aggregates on membrane bilayers at low nanomolar concentrations - a pathway in which the membrane plays the role of a catalyst. Additionally, physiological ionic conditions (150 mM NaCl) significantly enhance on-membrane aggregation, leading to the rapid formation of oligomers. The self-assembly process is reversible, so assembled aggregates can dissociate from the membrane surface into the bulk solution to further participate in the aggregation process. Molecular dynamics simulations demonstrate that the transient membrane-Aβ interaction dramatically changes the protein conformation, facilitating the assembly of dimers. The results indicate peptide–membrane interaction is the critical step towards oligomer formation at physiologically low protein concentrations.

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Section: Aggregation On Binary Slb Mixture (Popc:pops)mentioning

confidence: 83%

Section: Introductionmentioning

confidence: 99%

Interaction of Aβ42 with Membranes Triggers the Self-Assembly into Oligomers

Banerjee

Hashemi

Zagorski

et al. 2020

IJMS

View full text Add to dashboard Cite

show abstract

“…Aβ peptides were synthesized and provided by Dr. Zachary Wills from University of Pittsburgh. High performance liquid chromatography (HPLC), size exclusion chromatography (SEC) and electron microscopy (EM) were used to determine the concentration and oligomeric status of Aβ peptides as described in a recent publication [ 48 ]. Synthesized Aβ42 was dissolved in DMSO and aliquoted before freezing at −80 °C.…”

Section: Methodsmentioning

confidence: 99%

Abnormal dendritic calcium activity and synaptic depotentiation occur early in a mouse model of Alzheimer’s disease

Bai

Zhou

et al. 2017

Mol Neurodegeneration

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BackgroundAlzheimer’s disease (AD) is characterized by amyloid deposition, tangle formation as well as synapse loss. Synaptic abnormalities occur early in the pathogenesis of AD. Identifying early synaptic abnormalities and their underlying mechanisms is likely important for the prevention and treatment of AD.MethodsWe performed in vivo two-photon calcium imaging to examine the activities of somas, dendrites and dendritic spines of layer 2/3 pyramidal neurons in the primary motor cortex in the APPswe/PS1dE9 mouse model of AD and age-matched wild type control mice. We also performed calcium imaging to determine the effect of Aβ oligomers on dendritic calcium activity. In addition, structural and functional two-photon imaging were used to examine the link between abnormal dendritic calcium activity and changes in dendritic spine size in the AD mouse model.ResultsWe found that somatic calcium activities of layer 2/3 neurons were significantly lower in the primary motor cortex of 3-month-old APPswe/PS1dE9 mice than in wild type mice during quiet resting, but not during running on a treadmill. Notably, a significantly larger fraction of apical dendrites of layer 2/3 pyramidal neurons showed calcium transients with abnormally long duration and high peak amplitudes during treadmill running in AD mice. Administration of Aβ oligomers into the brain of wild type mice also induced abnormal dendritic calcium transients during running. Furthermore, we found that the activity and size of dendritic spines were significantly reduced on dendritic branches with abnormally prolonged dendritic calcium transients in AD mice.ConclusionOur findings show that abnormal dendritic calcium transients and synaptic depotentiation occur before amyloid plaque formation in the motor cortex of the APPswe/PS1dE9 mouse model of AD. Dendritic calcium transients with abnormally long durations and high amplitudes could be induced by soluble Aβ oligomers and contribute to synaptic deficits in the early pathogenesis of AD.Electronic supplementary materialThe online version of this article (10.1186/s13024-017-0228-2) contains supplementary material, which is available to authorized users.

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“…However, synaptic dysfunction by intracellular Aβ occurs long before neurodegeneration in Tg mice. In vitro studies have shown that extracellular Aβ oligomers alter synaptic spine density and morphology and disrupt axonal transport [48][49][50][51][52] and that these toxic effects are mediated by cell surface receptors, such as NMDAR [49,50], an ephrine receptor EphA4 [39], and a Nogo receptor NgR1 [53]. On the other hand, the effects of intracellular Aβ oligomers on synaptic spines and axonal transport were unclear.…”

Section: Cellular Modelsmentioning

confidence: 99%

APP Osaka Mutation in Familial Alzheimer’s Disease—Its Discovery, Phenotypes, and Mechanism of Recessive Inheritance

Tomiyama

Shimada

2020

IJMS

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Alzheimer’s disease is believed to begin with synaptic dysfunction caused by soluble Aβ oligomers. When this oligomer hypothesis was proposed in 2002, there was no direct evidence that Aβ oligomers actually disrupt synaptic function to cause cognitive impairment in humans. In patient brains, both soluble and insoluble Aβ species always coexist, and therefore it is difficult to determine which pathologies are caused by Aβ oligomers and which are caused by amyloid fibrils. Thus, no validity of the oligomer hypothesis was available until the Osaka mutation was discovered. This mutation, which was found in a Japanese pedigree of familial Alzheimer’s disease, is the deletion of codon 693 of APP gene, resulting in mutant Aβ lacking the 22nd glutamate. Only homozygous carriers suffer from dementia. In vitro studies revealed that this mutation has a very unique character that accelerates Aβ oligomerization but does not form amyloid fibrils. Model mice expressing this mutation demonstrated that all pathologies of Alzheimer’s disease can be induced by Aβ oligomers alone. In this review, we describe the story behind the discovery of the Osaka mutation, summarize the mutant’s phenotypes, and propose a mechanism of its recessive inheritance.

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Amyloid Beta Peptides Block New Synapse Assembly by Nogo Receptor-Mediated Inhibition of T-Type Calcium Channels

Cited by 41 publications

References 59 publications

Interaction of Aβ42 with Membranes Triggers the Self-Assembly into Oligomers

Interaction of Aβ42 with Membranes Triggers the Self-Assembly into Oligomers

Abnormal dendritic calcium activity and synaptic depotentiation occur early in a mouse model of Alzheimer’s disease

APP Osaka Mutation in Familial Alzheimer’s Disease—Its Discovery, Phenotypes, and Mechanism of Recessive Inheritance

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