Inactivation of seeding activity of amyloid β‐protein aggregates in vitro

2021 ◽  
Author(s):  
Hiroto Nakano ◽  
Tsuyoshi Hamaguchi ◽  
Tokuhei Ikeda ◽  
Takahiro Watanabe‐Nakayama ◽  
Kenjiro Ono ◽  
...  
Keyword(s):  
Amyloid Β ◽  
Protein Aggregates ◽  
Amyloid Β Protein ◽  
Β Protein

Chlorpromazine reduces toxicity and Ca2+ uptake induced by amyloid β protein (25–35) in vitro

1997 ◽  
Vol 748 (1-2) ◽  
pp. 184-188 ◽  
Author(s):  
Keiichi Ueda ◽  
Tatsurou Yagami ◽  
Kenji Asakura ◽  
Kazuo Kawasaki
Keyword(s):  
Amyloid Β ◽  
Amyloid Β Protein ◽  
Β Protein

Rifampicin Prevents the Aggregation and Neurotoxicity of Amyloid β Protein in Vitro

1994 ◽  
Vol 204 (1) ◽  
pp. 76-83 ◽  
Author(s):  
T. Tomiyama ◽  
S. Asano ◽  
Y. Suwa ◽  
T. Morita ◽  
K. Kataoka ◽  
...  
Keyword(s):  
Amyloid Β ◽  
Amyloid Β Protein ◽  
Β Protein

scholarly journals Upregulation of Alzheimer’s Disease Amyloid-β Protein Precursor in Astrocytes Both in vitro and in vivo

2020 ◽  
pp. 1-12 ◽  
Author(s):  
Yingxia Liang ◽  
Frank Raven ◽  
Joseph F. Ward ◽  
Sherri Zhen ◽  
Siyi Zhang ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Amyloid Β ◽  
Amyloid Β Protein ◽  
Protein Precursor ◽  
Β Protein

Novel mutations introduced at the β-site of amyloid β protein precursor enhance the production of amyloid β peptide by BACE1 in vitro and in cells

2005 ◽  
Vol 7 (2) ◽  
pp. 139-148 ◽  
Author(s):  
Xiao-Ping Shi ◽  
Katherine Tugusheva ◽  
James E. Bruce ◽  
Adam Lucka ◽  
Elizabeth Chen-Dodson ◽  
...  
Keyword(s):  
Amyloid Β ◽  
Amyloid Β Peptide ◽  
Amyloid Β Protein ◽  
Novel Mutations ◽  
Protein Precursor ◽  
Β Protein ◽  
In Cells

271 Pharmacological manipulation of Alzheimer's amyloid β protein in vitro and in vivo

1996 ◽  
Vol 17 (4) ◽  
pp. S68
Author(s):  
C.B. Eckman ◽  
C.-M. Prada ◽  
A. Fauq ◽  
S.G. Younkin
Keyword(s):  
Amyloid Β ◽  
Amyloid Β Protein ◽  
Pharmacological Manipulation ◽  
Β Protein

scholarly journals In vitro studies of amyloid β-protein fibril assembly and toxicity provide clues to the aetiology of Flemish variant (Ala692→Gly) Alzheimer's disease

2001 ◽  
Vol 355 (3) ◽  
pp. 869-877 ◽  
Author(s):  
Dominic M. WALSH ◽  
Dean M. HARTLEY ◽  
Margaret M. CONDRON ◽  
Dennis J. SELKOE ◽  
David B. TEPLOW
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Amino Acid ◽  
Amino Acid Substitution ◽  
Amyloid Β ◽  
In Vitro Studies ◽  
Amyloid Β Protein ◽  
Wild Type ◽  
Β Protein

In a Flemish kindred, an Ala692 → Gly amino acid substitution in the amyloid β-protein precursor (AβPP) causes a form of early-onset Alzheimer's disease (AD) which displays prominent amyloid angiopathy and unusually large senile plaque cores. The mechanistic basis of this Flemish form of AD is unknown. Previous in vitro studies of amyloid β-protein (Aβ) production in HEK-293 cells transfected with cDNA encoding Flemish AβPP have shown that full-length [Aβ(1–40)] and truncated [Aβ(5–40) and Aβ(11–40)] forms of Aβ are produced. In an effort to determine how these peptides might contribute to the pathogenesis of the Flemish disease, comparative biophysical and neurotoxicity studies were performed on wild-type and Flemish Aβ(1–40), Aβ(5–40) and Aβ(11–40). The results revealed that the Flemish amino acid substitution increased the solubility of each form of peptide, decreased the rate of formation of thioflavin-T-positive assemblies, and increased the SDS-stability of peptide oligomers. Although the kinetics of peptide assembly were altered by the Ala21 → Gly substitution, all three Flemish variants formed fibrils, as did the wild-type peptides. Importantly, toxicity studies using cultured primary rat cortical cells showed that the Flemish assemblies were as potent a neurotoxin as were the wild-type assemblies. Our results are consistent with a pathogenetic process in which conformational changes in Aβ induced by the Ala21 → Gly substitution would facilitate peptide adherence to the vascular endothelium, creating nidi for amyloid growth. Increased peptide solubility and assembly stability would favour formation of larger deposits and inhibit their elimination. In addition, increased concentrations of neurotoxic assemblies would accelerate neuronal injury and death.

scholarly journals The molecular tweezer CLR01 improves behavioral deficits and reduces tau pathology in P301S-tau transgenic mice

2021 ◽  
Vol 13 (1) ◽  
Author(s):  
Jing Di ◽  
Ibrar Siddique ◽  
Zizheng Li ◽  
Ghattas Malki ◽  
Simon Hornung ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Muscle Strength ◽  
Mouse Model ◽  
Amyloid Β ◽  
Amyloid Β Protein ◽  
Tau Pathology ◽  
Behavioral Deficits ◽  
Β Protein

Abstract Background Molecular tweezers (MTs) are broad-spectrum inhibitors of abnormal protein aggregation. A lead MT, called CLR01, has been demonstrated to inhibit the aggregation and toxicity of multiple amyloidogenic proteins in vitro and in vivo. Previously, we evaluated the effect of CLR01 in the 3 × Tg mouse model of Alzheimer’s disease, which overexpresses mutant human presenilin 1, amyloid β-protein precursor, and tau and found that subcutaneous administration of the compound for 1 month led to a robust reduction of amyloid plaques, neurofibrillary tangles, and microgliosis. CLR01 also has been demonstrated to inhibit tau aggregation in vitro and tau seeding in cell culture, yet because in Alzheimer’s disease (AD) and in the 3 × Tg model, tau hyperphosphorylation and aggregation are thought to be downstream of Aβ insults, the study in this model left open the question whether CLR01 affected tau in vivo directly or indirectly. Methods To determine if CLR01 could ameliorate tau pathology directly in vivo, we tested the compound similarly using the P301S-tau (line PS19) mouse model. Mice were administered 0.3 or 1.0 mg/kg per day CLR01 and tested for muscle strength and behavioral deficits, including anxiety- and disinhibition-like behavior. Their brains then were analyzed by immunohistochemical and biochemical assays for pathological forms of tau, neurodegeneration, and glial pathology. Results CLR01 treatment ameliorated muscle-strength deterioration, anxiety-, and disinhibition-like behavior. Improved phenotype was associated with decreased levels of pathologic tau forms, suggesting that CLR01 exerts a direct effect on tau in vivo. Limitations of the study included a relatively short treatment period of the mice at an age in which full pathology is not yet developed. In addition, high variability in this model lowered the statistical significance of the findings of some outcome measures. Conclusions The findings suggest that CLR01 is a particularly attractive candidate for the treatment of AD because it targets simultaneously the two major pathogenic proteins instigating and propagating the disease, amyloid β-protein (Aβ), and tau, respectively. In addition, our study suggests that CLR01 can be used for the treatment of other tauopathies in the absence of amyloid pathology.

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