Complexing Aβ Prevents the Cellular Anomalies Induced by the Peptide Alone

Henriques, Ana Gabriela; Oliveira, J. M.; Gomes, Bárbara; Ruivo, Raquel; Silva, E. F. da Cruz e; Silva, O. A. B. da Cruz e

doi:10.1007/s12031-014-0233-7

Cited by 7 publications

(7 citation statements)

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“…Lamin A mutants induce nuclear protein aggregation (Hubner et al ., 2006). Laminins complex with Aβ, preventing its fibril formation (Henriques et al ., 2014). Band 4.1‐like protein 1 binds and stabilizes dopamine receptors (Binda et al ., 2002).…”

Section: Discussionmentioning

confidence: 99%

Proteins that mediate protein aggregation and cytotoxicity distinguish Alzheimer's hippocampus from normal controls

et al. 2016

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SummaryNeurodegenerative diseases are distinguished by characteristic protein aggregates initiated by disease‐specific ‘seed’ proteins; however, roles of other co‐aggregated proteins remain largely unexplored. Compact hippocampal aggregates were purified from Alzheimer's and control‐subject pools using magnetic‐bead immunoaffinity pulldowns. Their components were fractionated by electrophoretic mobility and analyzed by high‐resolution proteomics. Although total detergent‐insoluble aggregates from Alzheimer's and controls had similar protein content, within the fractions isolated by tau or Aβ1–42 pulldown, the protein constituents of Alzheimer‐derived aggregates were more abundant, diverse, and post‐translationally modified than those from controls. Tau‐ and Aβ‐containing aggregates were distinguished by multiple components, and yet shared >90% of their protein constituents, implying similar accretion mechanisms. Alzheimer‐specific protein enrichment in tau‐containing aggregates was corroborated for individuals by three analyses. Five proteins inferred to co‐aggregate with tau were confirmed by precise in situ methods, including proximity ligation amplification that requires co‐localization within 40 nm. Nematode orthologs of 21 proteins, which showed Alzheimer‐specific enrichment in tau‐containing aggregates, were assessed for aggregation‐promoting roles in C. elegans by RNA‐interference ‘knockdown’. Fifteen knockdowns (71%) rescued paralysis of worms expressing muscle Aβ, and 12 (57%) rescued chemotaxis disrupted by neuronal Aβ expression. Proteins identified in compact human aggregates, bound by antibody to total tau, were thus shown to play causal roles in aggregation based on nematode models triggered by Aβ1–42. These observations imply shared mechanisms driving both types of aggregation, and/or aggregate‐mediated cross‐talk between tau and Aβ. Knowledge of protein components that promote protein accrual in diverse aggregate types implicates common mechanisms and identifies novel targets for drug intervention.

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Section: Discussionmentioning

confidence: 99%

Proteins that mediate protein aggregation and cytotoxicity distinguish Alzheimer's hippocampus from normal controls

et al. 2016

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“…On-bead peptoid library screening by Bezprozvanny et al resulted in selective and efficient binders IAM2 (7) and (IAM2) 2 (K d = 60 nM) for the Ab42 peptide. 97 Transthyretin (TTR) is a homotetrameric plasma protein (55 kDa) and plays an important role in neutralizing Ab toxicity by forming a stable complex with the Ab peptide. 92 In recent years cyclic peptides (CP) have emerged as a new class of powerful and specific amyloid modulators.…”

Section: View Article Onlinementioning

confidence: 99%

Function and toxicity of amyloid beta and recent therapeutic interventions targeting amyloid beta in Alzheimer's disease

2015

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Amyloidogenesis has been implicated in a broad spectrum of diseases in which amyloid protein is invariably misfolded and deposited in cells and organs. Alzheimer's disease is one of the most devastating ailments among amyloidogenesis induced dementia. The amyloid beta (Aβ) peptide derived from amyloid precursor protein (APP) is misfolded and deposited as plaques in the brain, which are said to be the hallmark of Alzheimer's disease. In normal brains physiological concentration of the Aβ peptide has been indicated to be involved in modulating neurogenesis and synaptic plasticity. However, excess Aβ production, its aggregation and deposition deleteriously affect a large number of biologically important pathways leading to neuronal cell death. Targeting Aβ production, Aβ aggregation or its clearance from the brain has been an active area of research for preventing or curing AD. Our Feature Article intends to detail the aggregation mechanism, the physiological role of the Aβ peptide, elaborate its toxic effects, and outline the different classes of molecules designed in the last two years to inhibit amyloidogenic APP processing, Aβ oligomerization or fibrillogenesis and to modulate different pathways for active clearance of Aβ from the brain.

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“…Senile plaques are extracellular deposits of Aβ in the brain associated with degenerative neurons and an abundance of microglia and astrocytes (3). As a neurodegenerative disorder, AD is associated with the presence of these neurotoxic senile plaques in the brain (4). Oxidative stress is another important independent adverse factor in the development of AD (5).…”

Section: Introductionmentioning

confidence: 99%

Catalpol preserves neural function and attenuates the pathology of Alzheimer's disease in mice

Huang

Xiang

et al. 2015

Molecular Medicine Reports

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Alzheimer's disease (AD) is the most common form of dementia and there currently are no effective treatment strategies available. Catalpol is an iridoid glucoside, and large quantities can be isolated from the genus Rehmannia (Orobanchaceae). The present study assessed whether catalpol had any protective effects against Alzheimer's disease using a murine model. Reactive oxygen species (ROS)-associated enzymes as well as soluble Aβ40 and Aβ42 were detected using kits. Thioflavin‑S staining was performed to detect senile plaques and reverse-transcription quantitative polymerase chain reaction was used to assess iroquois homeobox protein 3 (IRX3) and obesity‑associated genes, while western blot analysis was used for β‑secretase 1 (BACE1), insulin‑degrading enzyme (IDE) and neprilysin (NEP) detection. The Morris water maze was used to detect the learning ability and spatial memory. The results revealed that catalpol was able to reduce the oxidative stress in the cerebral cortex by regulating the activities and concentration of ROS‑associated enzymes superoxide dismutase, glutathione peroxidase and catalase, however not malondialdehyde. Catalpol was also identified to be able to reduce the levels of soluble Aβ40 and Aβ42 in the cerebral cortex and thus inhibit the formation of senile plaques. These effects were observed to be regulated by IDE, however not by BACE1 or NEP. It is suggested that catalpol is not capable of directly regulating the expression of IRX3 and obesity‑associated genes. Subsequent to the treatment with catalpol, impairments in learning and memory were also observed to be relieved using the Morris water maze test. The results of the present study indicate that catalpol may be a potential drug for the treatment of neurodegenerative diseases such as AD.

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Complexing Aβ Prevents the Cellular Anomalies Induced by the Peptide Alone

Cited by 7 publications

References 50 publications

Proteins that mediate protein aggregation and cytotoxicity distinguish Alzheimer's hippocampus from normal controls

Proteins that mediate protein aggregation and cytotoxicity distinguish Alzheimer's hippocampus from normal controls

Function and toxicity of amyloid beta and recent therapeutic interventions targeting amyloid beta in Alzheimer's disease

Catalpol preserves neural function and attenuates the pathology of Alzheimer's disease in mice

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