scholarly journals Combating the amyloid-induced cellular toxicity and stiffness by designer peptidomimetics

2022 ◽  
Author(s):  
Mouli Konar ◽  
Debasis Ghosh ◽  
Sourav Samanta ◽  
T. Govindaraju
Keyword(s):  
Adverse Effects ◽  
Amyloid Beta ◽  
Cellular Stress ◽  
Neuronal Cells ◽  
Cellular Toxicity ◽  
Aβ Aggregation

Amyloid beta (Aβ) aggregation species-associated cellular stress instigates cytotoxicity and adverse cellular stiffness to neuronal cells. The study and modulation of these adverse effects demand immediate attention to tackle Alzheimer’s...

scholarly journals The inhibition of cellular toxicity of amyloid-beta by dissociated transthyretin

2019 ◽  
Author(s):  
Qin Cao ◽  
Daniel H. Anderson ◽  
Wilson Liang ◽  
Joshua Chou ◽  
Lorena Saelices
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Amyloid Beta ◽  
Amyloid Plaques ◽  
Inhibitory Effect ◽  
Aβ Oligomers ◽  
Transthyretin Amyloidosis ◽  
Cellular Toxicity ◽  
Aβ Aggregation

AbstractThe protective effect of transthyretin (TTR) on cellular toxicity of amyloid-beta (Aβ) has been previously reported. TTR is a tetrameric carrier of thyroxine in blood and cerebrospinal fluid, whose pathogenic aggregation causes systemic amyloidosis. In contrast, many reports have shown that TTR binds amyloid-beta (Aβ), associated with Alzheimer’s disease, alters its aggregation, and inhibits its toxicity both in vitro and in vivo. In this study, we question whether TTR amyloidogenic ability and its anti-amyloid inhibitory effect are associated. Our results indicate that the dissociation of the TTR tetramer, required for its amyloid pathogenesis, is also necessary to prevent cellular toxicity from Aβ oligomers. These findings suggest that the Aβ binding site of TTR may be hidden in its tetrameric form. Aided by computational docking and peptide screening, we identified a TTR segment that is capable of altering Aβ aggregation and toxicity, mimicking TTR cellular protection. This segment inhibits Aβ oligomer formation and also promotes the formation of non-toxic, non-amyloid, amorphous aggregates which are more sensitive to protease digestion. This segment also inhibits seeding of Aβ catalyzed by Aβ fibrils extracted from the brain of an Alzheimer’s patient. Our results suggest that mimicking the inhibitory effect of TTR with peptide-based therapeutics represents an additional avenue to explore for the treatment of Alzheimer’s disease.Significance statementThe pathological landmarks of Alzheimer’s disease are the formation of amyloid plaques and neurofibrillary tangles. Amyloid plaques contain fibrous structures made of aggregated amyloid-beta (Aβ). In 1982, Shirahama and colleagues observed the presence of transthyretin (TTR) in these plaques. TTR is a tetrameric protein whose aggregation causes transthyretin amyloidosis. However, TTR protects Aβ from aggregating and causing toxicity to neurons. In this study, we show that the dissociation of TTR tetramers is required to inhibit cellular toxicity caused by Aβ. In addition, we identified a minimum segment of TTR that inhibits Aβ aggregation and cellular toxicity by the formation of amorphous aggregates that are sensitive to proteases, similar to the natural effect of TTR found by others in vivo.

scholarly journals Flavan‐3‐ol Microbial Metabolites Modulate Proteolysis in Neuronal Cells Reducing Amyloid‐beta (1‐42) Levels

2021 ◽  
pp. 2100380
Author(s):  
Valentina Cecarini ◽  
Massimiliano Cuccioloni ◽  
Yadong Zheng ◽  
Laura Bonfili ◽  
Chunmei Gong ◽  
...  
Keyword(s):  
Amyloid Beta ◽  
Neuronal Cells ◽  
Microbial Metabolites

Neuroinflammation and Alzheimer’s disease: lessons learned from 5-lipoxygenase

2014 ◽  
Vol 5 (3) ◽  
Author(s):  
Yash Joshi ◽  
Domenico Praticò
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Animal Models ◽  
Amyloid Beta ◽  
Neuronal Cells ◽  
Lessons Learned ◽  
Brain Inflammation ◽  
Complex Relationship ◽  
Amyloid Hypothesis

AbstractAside from the well-known amyloid beta and tau pathologies found in Alzheimer’s disease (AD), neuroinflammation is a well-established aspect described in humans and animal models of the disease. Inflammatory perturbations are evident not only in neurons, but also in non-neuronal cells and cytokines in the AD brain. Although the amyloid hypothesis implicates amyloid beta (Aβ) as the prime initiator of the AD, brain inflammation in AD has a complex relationship between Aβ and tau. Using our work with the 5-lipoxygenase protein as an example, we suggest that at least in the case of AD, there is an interdependent and not necessarily hierarchical pathological relationship between Aβ, tau and inflammation.

scholarly journals -Secretase Modulators: Can We Combine Potency with Safety?

2012 ◽  
Vol 2012 ◽  
pp. 1-10 ◽  
Author(s):  
Harrie J. M. Gijsen ◽  
Marc Mercken
Keyword(s):  
Adverse Effects ◽  
Amyloid Beta ◽  
Proteolytic Processing ◽  
Considerable Progress ◽  
Phase Iii ◽  
Phase Iii Trial ◽  
Safety Margins ◽  
Disease Modifying

-Secretase modulation has been proposed as a potential disease modifying anti-Alzheimer’s approach. -Secretase modulators (GSMs) cause a product shift from the longer amyloid-beta (Aβ) peptide isoforms to shorter, more soluble, and less amyloidogenic isoforms, without inhibiting APP or Notch proteolytic processing. As such, modulating -secretase may avoid some of the adverse effects observed with -secretase inhibitors. Since the termination of the GSM tarenfurbil in 2008 due to negative phase III trial results, a considerable progress has been made towards more potent and better brain penetrable compounds. However, an analysis of their lipophilic efficiency indices indicates that their increased potency can be largely attributed to their increased lipophilicity. The need for early and chronic dosing with GSMs will require high-safety margins. This will be a challenge to achieve with the current, highly lipophilic GSMs. We will demonstrate that by focusing on the drug-like properties of GSMs, a combination of highin vitropotency and reduced lipophilicity can be achieved and does result in better tolerated compounds. The next hurdle will be to translate this knowledge into GSMs which are highly efficacious and safein vivo.

scholarly journals P1-269: Structural basis for amyloid beta binding to neuronal cells

2010 ◽  
Vol 6 ◽  
pp. S252-S252
Author(s):  
Lorena Perrone ◽  
Dirk Bartnik ◽  
Honoree Marzaguil ◽  
Susanne A. Funke ◽  
Paolo Gubellini ◽  
...  
Keyword(s):  
Amyloid Beta ◽  
Neuronal Cells ◽  
Structural Basis
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