scholarly journals A rationally designed bicyclic peptide remodels Aβ42 aggregation in vitro and reduces its toxicity in a worm model of Alzheimer’s disease

2020 ◽  
Vol 10 (1) ◽  
Author(s):  
Tatsuya Ikenoue ◽  
Francesco A. Aprile ◽  
Pietro Sormanni ◽  
Francesco S. Ruggeri ◽  
Michele Perni ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Rational Design ◽  
Therapeutic Potential ◽  
Amyloid Β ◽  
Disordered Proteins ◽  
Amyloid Β Peptide ◽  
Model Of Alzheimer’S Disease ◽  
Worm Model

Abstract Bicyclic peptides have great therapeutic potential since they can bridge the gap between small molecules and antibodies by combining a low molecular weight of about 2 kDa with an antibody-like binding specificity. Here we apply a recently developed in silico rational design strategy to produce a bicyclic peptide to target the C-terminal region (residues 31–42) of the 42-residue form of the amyloid β peptide (Aβ42), a protein fragment whose aggregation into amyloid plaques is linked with Alzheimer’s disease. We show that this bicyclic peptide is able to remodel the aggregation process of Aβ42 in vitro and to reduce its associated toxicity in vivo in a C. elegans worm model expressing Aβ42. These results provide an initial example of a computational approach to design bicyclic peptides to target specific epitopes on disordered proteins.

scholarly journals MMP13 inhibition rescues cognitive decline in Alzheimer transgenic mice via BACE1 regulation

Brain ◽  
2018 ◽  
Vol 142 (1) ◽  
pp. 176-192 ◽  
Author(s):  
Bing-Lin Zhu ◽  
Yan Long ◽  
Wei Luo ◽  
Zhen Yan ◽  
Yu-Jie Lai ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Therapeutic Potential ◽  
Amyloid Β ◽  
Translation Initiation Factor ◽  
Precursor Protein ◽  
Initiation Factor ◽  
Luciferase Reporter ◽  
Protein Levels ◽  
Model Of Alzheimer’S Disease

AbstractMMP13 (matrix metallopeptidase 13) plays a key role in bone metabolism and cancer development, but has no known functions in Alzheimer’s disease. In this study, we used high-throughput small molecule screening in SH-SY5Y cells that stably expressed a luciferase reporter gene driven by the BACE1 (β-site amyloid precursor protein cleaving enzyme 1) promoter, which included a portion of the 5′ untranslated region (5′UTR). We identified that CL82198, a selective inhibitor of MMP13, decreased BACE1 protein levels in cultured neuronal cells. This effect was dependent on PI3K (phosphatidylinositide 3-kinase) signalling, and was unrelated to BACE1 gene transcription and protein degradation. Further, we found that eukaryotic translation initiation factor 4B (eIF4B) played a key role, as the mutation of eIF4B at serine 422 (S422R) or deletion of the BACE1 5′UTR attenuated MMP13-mediated BACE1 regulation. In APPswe/PS1E9 mice, an animal model of Alzheimer’s disease, hippocampal Mmp13 knockdown or intraperitoneal CL82198 administration reduced BACE1 protein levels and the related amyloid-β precursor protein processing, amyloid-β load and eIF4B phosphorylation, whereas spatial and associative learning and memory performances were improved. Collectively, MMP13 inhibition/CL82198 treatment exhibited therapeutic potential for Alzheimer’s disease, via the translational regulation of BACE1.

scholarly journals Increased levels of Stress-inducible phosphoprotein-1 accelerates amyloid-β deposition in a mouse model of Alzheimer’s disease

2020 ◽  
Vol 8 (1) ◽  
Author(s):  
Rachel E. Lackie ◽  
Jose Marques-Lopes ◽  
Valeriy G. Ostapchenko ◽  
Sarah Good ◽  
Wing-Yiu Choy ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Mouse Model ◽  
Protein Quality ◽  
Amyloid Β ◽  
Amyloid Burden ◽  
C Elegans ◽  
Model Of Alzheimer’S Disease

Abstract Molecular chaperones and co-chaperones, which are part of the protein quality control machinery, have been shown to regulate distinct aspects of Alzheimer’s Disease (AD) pathology in multiple ways. Notably, the co-chaperone STI1, which presents increased levels in AD, can protect mammalian neurons from amyloid-β toxicity in vitro and reduced STI1 levels worsen Aβ toxicity in C. elegans. However, whether increased STI1 levels can protect neurons in vivo remains unknown. We determined that overexpression of STI1 and/or Hsp90 protected C. elegans expressing Aβ(3–42) against Aβ-mediated paralysis. Mammalian neurons were also protected by elevated levels of endogenous STI1 in vitro, and this effect was mainly due to extracellular STI1. Surprisingly, in the 5xFAD mouse model of AD, by overexpressing STI1, we find increased amyloid burden, which amplifies neurotoxicity and worsens spatial memory deficits in these mutants. Increased levels of STI1 disturbed the expression of Aβ-regulating enzymes (BACE1 and MMP-2), suggesting potential mechanisms by which amyloid burden is increased in mice. Notably, we observed that STI1 accumulates in dense-core AD plaques in both 5xFAD mice and human brain tissue. Our findings suggest that elevated levels of STI1 contribute to Aβ accumulation, and that STI1 is deposited in AD plaques in mice and humans. We conclude that despite the protective effects of STI1 in C. elegans and in mammalian cultured neurons, in vivo, the predominant effect of elevated STI1 is deleterious in AD.

Netrin-1 Interrupts Amyloid-β Amplification, Increases sAβPPα in vitro and in vivo, and Improves Cognition in a Mouse Model of Alzheimer’s Disease

2016 ◽  
Vol 52 (1) ◽  
pp. 223-242 ◽  
Author(s):  
Patricia R. Spilman ◽  
Veronique Corset ◽  
Olivia Gorostiza ◽  
Karen S. Poksay ◽  
Veronica Galvan ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Mouse Model ◽  
Amyloid Β ◽  
Model Of Alzheimer’S Disease

scholarly journals Plant sphingolipids promote extracellular vesicle release and alleviate amyloid-β pathologies in a mouse model of Alzheimer’s disease

2019 ◽  
Vol 9 (1) ◽  
Author(s):  
Kohei Yuyama ◽  
Kaori Takahashi ◽  
Seigo Usuki ◽  
Daisuke Mikami ◽  
Hui Sun ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Amyloid Β ◽  
Neuronal Cultures ◽  
Amyloid Β Protein ◽  
Neuronal Marker ◽  
Enhanced Production ◽  
Model Of Alzheimer’S Disease ◽  
Aβ Clearance

AbstractThe accumulation of amyloid-β protein (Aβ) in brain is linked to the early pathogenesis of Alzheimer’s disease (AD). We previously reported that neuron-derived exosomes promote Aβ clearance in the brains of amyloid precursor protein transgenic mice and that exosome production is modulated by ceramide metabolism. Here, we demonstrate that plant ceramides derived from Amorphophallus konjac, as well as animal-derived ceramides, enhanced production of extracellular vesicles (EVs) in neuronal cultures. Oral administration of plant glucosylceramide (GlcCer) to APP overexpressing mice markedly reduced Aβ levels and plaque burdens and improved cognition in a Y-maze learning task. Moreover, there were substantial increases in the neuronal marker NCAM-1, L1CAM, and Aβ in EVs isolated from serum and brain tissues of the GlcCer-treated AD model mice. Our data showing that plant ceramides prevent Aβ accumulation by promoting EVs-dependent Aβ clearance in vitro and in vivo provide evidence for a protective role of plant ceramides in AD. Plant ceramides might thus be used as functional food materials to ameliorate AD pathology.

The prion-like properties of amyloid-beta peptide and Tau: Is there any risk of transmitting Alzheimer's disease during neurosurgical interventions?

2020 ◽  
Vol 17 ◽  
Author(s):  
Padilla-Zambrano H ◽  
García-Ballestas E ◽  
Quiñones-Ossa GA ◽  
Sibaja-Perez A ◽  
Agrawal A ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Prion Diseases ◽  
Amyloid Β ◽  
Public Health Issue ◽  
Amyloid Β Peptide ◽  
Neurosurgical Procedure ◽  
Beta Peptide

: Recent studies have recognized similarities between the peptides involved in the neuropathology of Alzheimer’s disease and prions. The Tau protein and the Amyloid β peptide represent the theoretical pillars of Alzheimer’s disease development. It is probable that there is a shared mechanism for the transmission of these substances and the prion diseases development; this presumption is based on the presentation of several cases of individuals without risk factors who developed dementia decades after a neurosurgical procedure. This article aims to present the role of Aβ and Tau, which underlie the pathophysiologic mechanisms involved in the AD and their similarities with the prion diseases infective mechanisms by means of the presentation of the available evidence at molecular (in-vitro), animal, and human levels that support the controversy on whether these diseases might be transmitted in neurosurgical interventions, which may constitute a wide public health issue.

scholarly journals CNI-1493 inhibits Aβ production, plaque formation, and cognitive deterioration in an animal model of Alzheimer's disease

2008 ◽  
Vol 205 (7) ◽  
pp. 1593-1599 ◽  
Author(s):  
Michael Bacher ◽  
Richard Dodel ◽  
Bayan Aljabari ◽  
Kathy Keyvani ◽  
Philippe Marambaud ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Memory Performance ◽  
Amyloid Β ◽  
Amyloid Plaque ◽  
Amyloid Β Protein ◽  
Aβ Oligomers ◽  
App Processing ◽  
Model Of Alzheimer’S Disease

Alzheimer's disease (AD) is characterized by neuronal atrophy caused by soluble amyloid β protein (Aβ) peptide “oligomers” and a microglial-mediated inflammatory response elicited by extensive amyloid deposition in the brain. We show that CNI-1493, a tetravalent guanylhydrazone with established antiinflammatory properties, interferes with Aβ assembly and protects neuronal cells from the toxic effect of soluble Aβ oligomers. Administration of CNI-1493 to TgCRND8 mice overexpressing human amyloid precursor protein (APP) for a treatment period of 8 wk significantly reduced Aβ deposition. CNI-1493 treatment resulted in 70% reduction of amyloid plaque area in the cortex and 87% reduction in the hippocampus of these animals. Administration of CNI-1493 significantly improved memory performance in a cognition task compared with vehicle-treated mice. In vitro analysis of CNI-1493 on APP processing in an APP-overexpressing cell line revealed a significant dose-dependent decrease of total Aβ accumulation. This study indicates that the antiinflammatory agent CNI-1493 can ameliorate the pathophysiology and cognitive defects in a murine model of AD.

scholarly journals Naphthalene monoimide derivative ameliorates amyloid burden and cognitive decline in a transgenic mouse model of Alzheimer’s disease

2020 ◽  
Author(s):  
Sourav Samanta ◽  
Kolla Rajasekhar ◽  
Madhu Ramesh ◽  
N. Arul Murugan ◽  
Shadab Alam ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Cognitive Deficits ◽  
Neurodegenerative Disorder ◽  
Amyloid Β ◽  
Salt Bridges ◽  
Amyloid Burden ◽  
Amyloid Toxicity ◽  
Model Of Alzheimer’S Disease

ABSTRACTAlzheimer’s disease (AD) is a major neurodegenerative disorder and the leading cause of dementia worldwide. Predominantly, misfolding and aggregation of amyloid-β (Aβ) peptides associated with multifaceted toxicity is the neuropathological hallmark of AD pathogenesis and thus, primary therapeutic target to ameliorate neuronal toxicity and cognitive deficits. Herein, we report the design, synthesis and evaluation of small molecule inhibitors with naphthalene monoimide scaffold to ameliorate in vitro and in vivo amyloid induced neurotoxicity. The detailed studies established TGR63 as the lead candidate to rescue neuronal cells from amyloid toxicity. The in silico studies showed disruption of salt bridges and intermolecular hydrogen bonding interactions within Aβ42 fibrils by the interaction of TGR63, causing destabilization of Aβ42 assembly. Remarkably, TGR63 treatment showed a significant reduction in cortical and hippocampal amyloid burden in the progressive stages of APP/PS1 AD mice brain. Various behavioral tests demonstrated rescued cognitive deficits. The excellent biocompatibility, BBB permeability and therapeutic efficacy to reduce amyloid burden make TGR63 a promising candidate for the treatment of AD.

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