scholarly journals Rescue of cognitive deficits in APP/PS1 mice by accelerating the aggregation of β-amyloid peptide

2019 ◽  
Vol 11 (1) ◽  
Author(s):  
Jian-Xiang Zhang ◽  
Yi-Hui Lai ◽  
Pan-Ying Mi ◽  
Xue-Ling Dai ◽  
Ran Zhang ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Brain Tissue ◽  
Amyloid Peptide ◽  
Flavonoid Compound ◽  
Protective Effects ◽  
Behavioral Experiments ◽  
Aβ Oligomers ◽  
Amyloid Aβ ◽  
Β Amyloid

Abstract Background Brain amyloid deposition is one of the main pathological characteristics of Alzheimer’s disease (AD). Soluble oligomers formed during the process that causes β-amyloid (Aβ) to aggregate into plaques are considered to have major neurotoxicity. Currently, drug development for the treatment of Alzheimer’s disease has encountered serious difficulties. Our newly proposed solution is to accelerate the aggregation of Aβ to reduce the amount of cytotoxic Aβ oligomers in brain tissue. This strategy differs from the existing strategy of reducing the total Aβ content and the number of amyloid plaques. Method In this study, we screened a small library and found that a flavonoid compound (ZGM1) promoted the aggregation of β-amyloid (Aβ). We further verified the binding of ZGM1 to Aβ42 using a microscale thermophoresis (MST) assay. Subsequently, we used dot blotting (DB), transmission electron microscopy (TEM), and thioflavin T fluorescence (ThT) measurements to study the aggregation of Aβ under the influence of ZGM1. By using cell experiments, we determined whether ZGM1 can inhibit the cytotoxicity of Aβ. Finally, we studied the protective effects of ZGM1 on cognitive function in APPswe/PS1 mice via behavioral experiments and measured the number of plaques in the mouse brain by thioflavin staining. Results ZGM1 can bind with Aβ directly and mediate a new Aβ assembly process to form reticular aggregates and reduce the amount of Aβ oligomers. Animal experiments showed that ZGM1 can significantly improve cognitive dysfunction and that Aβ plaque deposition in the brain tissue of mice in the drug-administered group was significantly increased. Conclusion Our research suggests that promoting Aβ aggregation is a promising treatment method for AD and deserves further investigation.

scholarly journals Macroautophagy—a novel β-amyloid peptide-generating pathway activated in Alzheimer's disease

2005 ◽  
Vol 171 (1) ◽  
pp. 87-98 ◽  
Author(s):  
W. Haung Yu ◽  
Ana Maria Cuervo ◽  
Asok Kumar ◽  
Corrinne M. Peterhoff ◽  
Stephen D. Schmidt ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Cell Survival ◽  
Mammalian Target Of Rapamycin ◽  
Amyloid Peptide ◽  
Survival Pathways ◽  
Secretase Activity ◽  
Amyloid Aβ ◽  
Β Amyloid ◽  
Β Amyloid Peptide

Macroautophagy, which is a lysosomal pathway for the turnover of organelles and long-lived proteins, is a key determinant of cell survival and longevity. In this study, we show that neuronal macroautophagy is induced early in Alzheimer's disease (AD) and before β-amyloid (Aβ) deposits extracellularly in the presenilin (PS) 1/Aβ precursor protein (APP) mouse model of β-amyloidosis. Subsequently, autophagosomes and late autophagic vacuoles (AVs) accumulate markedly in dystrophic dendrites, implying an impaired maturation of AVs to lysosomes. Immunolabeling identifies AVs in the brain as a major reservoir of intracellular Aβ. Purified AVs contain APP and β-cleaved APP and are highly enriched in PS1, nicastrin, and PS-dependent γ-secretase activity. Inducing or inhibiting macroautophagy in neuronal and nonneuronal cells by modulating mammalian target of rapamycin kinase elicits parallel changes in AV proliferation and Aβ production. Our results, therefore, link β-amyloidogenic and cell survival pathways through macroautophagy, which is activated and is abnormal in AD.

A spiropyran-based fluorescent probe for the specific detection of β-amyloid peptide oligomers in Alzheimer's disease

2016 ◽  
Vol 52 (57) ◽  
pp. 8865-8868 ◽  
Author(s):  
Guanglei Lv ◽  
Anyang Sun ◽  
Peng Wei ◽  
Ning Zhang ◽  
Haichuang Lan ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Fluorescent Probe ◽  
Amyloid Peptide ◽  
Specific Detection ◽  
Aβ Oligomers ◽  
Β Amyloid ◽  
Β Amyloid Peptide

A fluorescent probe for the specific detection of Aβ oligomers in Alzheimer's disease both in vitro and in vivo was developed.

MiR-335-5p Inhibits β-Amyloid (Aβ) Accumulation to Attenuate Cognitive Deficits Through Targeting c-jun-N-terminal Kinase 3 in Alzheimer’s Disease

2020 ◽  
Vol 17 (1) ◽  
pp. 93-101 ◽  
Author(s):  
Dan Wang ◽  
Zhifu Fei ◽  
Song Luo ◽  
Hai Wang
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Transgenic Mice ◽  
Western Blot ◽  
Mrna Expression ◽  
Cognitive Deficits ◽  
Protein Levels ◽  
Amyloid Aβ ◽  
Β Amyloid ◽  
The Relationship

Objectives: Alzheimer's disease (AD), also known as senile dementia, is a common neurodegenerative disease characterized by progressive cognitive impairment and personality changes. Numerous evidences have suggested that microRNAs (miRNAs) are involved in the pathogenesis and development of AD. However, the exact role of miR-335-5p in the progression of AD is still not clearly clarified. Methods: The protein and mRNA levels were measured by western blot and RNA extraction and quantitative real-time PCR (qRT-PCR), respectively. The relationship between miR-335-5p and c-jun-N-terminal kinase 3 (JNK3) was confirmed by dual-luciferase reporter assay. SH-SY5Y cells were transfected with APP mutant gene to establish the in vitro AD cell model. Flow cytometry and western blot were performed to evaluate cell apoptosis. The APP/PS1 transgenic mice were used as an in vivo AD model. Morris water maze test was performed to assess the effect of miR- 335-5p on the cognitive deficits in APP/PS1 transgenic mice. Results: The JNK3 mRNA expression and protein levels of JNK3 and β-Amyloid (Aβ) were significantly up-regulated, and the mRNA expression of miR-335-5p was down-regulated in the brain tissues of AD patients. The expression levels of miR-335-5p and JNK3 were significantly inversely correlated. Further, the dual Luciferase assay verified the relationship between miR-335- 5p and JNK3. Overexpression of miR-335-5p significantly decreased the protein levels of JNK3 and Aβ and inhibited apoptosis in SH-SY5Y/APPswe cells, whereas the inhibition of miR-335-5p obtained the opposite results. Moreover, the overexpression of miR-335-5p remarkably improved the cognitive abilities of APP/PS1 mice. Conclusion: The results revealed that the increased JNK3 expression, negatively regulated by miR-335-5p, may be a potential mechanism that contributes to Aβ accumulation and AD progression, indicating a novel approach for AD treatment.

Pentapeptide Amides Interfere with the Aggregation of β-Amyloid Peptide of Alzheimer's Disease

2002 ◽  
Vol 292 (4) ◽  
pp. 931-936 ◽  
Author(s):  
Csaba Hetényi ◽  
Zoltán Szabó ◽  
Éva Klement ◽  
Zsolt Datki ◽  
Tamás Körtvélyesi ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Amyloid Peptide ◽  
Β Amyloid ◽  
Β Amyloid Peptide

Distance-based β-amyloid protein detection on PADs for scanning and subsequent follow up of Alzheimer’s disease in human urine sample

The Analyst ◽  
2022 ◽  
Author(s):  
Kawin Khachornsakkul ◽  
Anongnat Tiangtrong ◽  
Araya Suwannasom ◽  
Wuttichai Sangkharoek ◽  
Opor Jamjumrus ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Human Urine ◽  
Protein Detection ◽  
Protein Quantification ◽  
Amyloid Protein ◽  
Human Urine Sample ◽  
Amyloid Aβ ◽  
Β Amyloid

We report on the first development of a simple distance-based β-amyloid (Aβ) protein quantification using paper-based devices (dPADs) to screen for Alzheimer’s disease (AD) and to subsequently follow up on...

Strength training or green tea prevent memory deficits in a β-amyloid peptide-mediated Alzheimer's disease model

2021 ◽  
Vol 143 ◽  
pp. 111186
Author(s):  
Helen L. Schimidt ◽  
Guilherme S. Carrazoni ◽  
Alexandre Garcia ◽  
Ivan Izquierdo ◽  
Pâmela B. Mello-Carpes ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Strength Training ◽  
Green Tea ◽  
Disease Model ◽  
Memory Deficits ◽  
Amyloid Peptide ◽  
Β Amyloid ◽  
Β Amyloid Peptide

scholarly journals Noncanonical function of an autophagy protein prevents spontaneous Alzheimer’s disease

2020 ◽  
Vol 6 (33) ◽  
pp. eabb9036
Author(s):  
Bradlee L. Heckmann ◽  
Brett J. W. Teubner ◽  
Emilio Boada-Romero ◽  
Bart Tummers ◽  
Clifford Guy ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Human Disease ◽  
Memory Impairment ◽  
Memory Loss ◽  
Tau Hyperphosphorylation ◽  
Primary Microglia ◽  
Amyloid Aβ ◽  
Β Amyloid ◽  
Old Mice

Noncanonical functions of autophagy proteins have been implicated in neurodegenerative conditions, including Alzheimer’s disease (AD). The WD domain of the autophagy protein Atg16L is dispensable for canonical autophagy but required for its noncanonical functions. Two-year-old mice lacking this domain presented with robust β-amyloid (Aβ) pathology, tau hyperphosphorylation, reactive microgliosis, pervasive neurodegeneration, and severe behavioral and memory deficiencies, consistent with human disease. Mechanistically, we found this WD domain was required for the recycling of Aβ receptors in primary microglia. Pharmacologic suppression of neuroinflammation reversed established memory impairment and markers of disease pathology in this novel AD model. Therefore, loss of the Atg16L WD domain drives spontaneous AD in mice, and inhibition of neuroinflammation is a potential therapeutic approach for treating neurodegeneration and memory loss. A decline in expression of ATG16L in the brains of human patients with AD suggests the possibility that a similar mechanism may contribute in human disease.

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