Dataset Information

Rescue of cognitive deficits in APP/PS1 mice by accelerating the aggregation of ?-amyloid peptide.

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 ?-amyloid (A?) 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 A? to reduce the amount of cytotoxic A? oligomers in brain tissue. This strategy differs from the existing strategy of reducing the total A? 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 ?-amyloid (A?). We further verified the binding of ZGM1 to A?42 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 A? under the influence of ZGM1. By using cell experiments, we determined whether ZGM1 can inhibit the cytotoxicity of A?. 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 A? directly and mediate a new A? assembly process to form reticular aggregates and reduce the amount of A? oligomers. Animal experiments showed that ZGM1 can significantly improve cognitive dysfunction and that A? plaque deposition in the brain tissue of mice in the drug-administered group was significantly increased.

Conclusion

Our research suggests that promoting A? aggregation is a promising treatment method for AD and deserves further investigation.

SUBMITTER: Zhang JX

PROVIDER: S-EPMC6918606 | biostudies-literature | 2019 Dec

REPOSITORIES: biostudies-literature

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Publications

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

Zhang Jian-Xiang JX Lai Yi-Hui YH Mi Pan-Ying PY Dai Xue-Ling XL Zhang Ran R Zhang Zhan-Jun ZJ Zhang Shu-Juan SJ Zhang Xi-Wen XW Zhang Xi-Yan XY Yang Bing-Yu BY Cui Dong-Mei DM Zhang Chen C Zhao Chang-Qi CQ Dou Fei F

Alzheimer's research & therapy 20191217 1

<h4>Background</h4>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. ...[more]

PMID: 31847879

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Project description:BackgroundAmyloid beta (Aβ) which is recognized as a main feature of Alzheimer's disease (AD) has been proposed to "spread" through anatomically and functionally connected brain regions. The entorhinal cortex and perforant path are the earliest affected brain regions in AD. The perforant path is the most vulnerable circuit in the cortex with respect to both aging and AD. Previous data show that the origins and terminations of the perforant path are susceptible to amyloid deposition at the younger age in AD. Nogo receptor (NgR) plays an essential role in limiting injury-induced axonal growth and experience-dependent plasticity in the adult brain. It has been suggested that NgR is involved in AD pathological features, but the results have been conflicting and the detailed mechanism needs further investigation. In this study, the effect of NgR in the perforant path on the pathological and functional phenotype of APP/PS1 transgenic mice was studied.MethodsTo genetically manipulate NgR expression, adeno-associated virus (AAV) with short hairpin (shRNA) against NgR was injected into the perforant path of APP/PS1 transgenic mice, followed by an assessment of behavioral, synaptic plasticity and neuropathological phenotypes. NgR was overexpressed or knockdown in neuroblastoma N2a cells and APPswe/HEK293 cells to investigate the interaction between NgR and amyloid precursor protein (APP).ResultsIt is shown that reduction of NgR in the perforant path rescued cognitive and synaptic deficits in APP/PS1 transgenic mice. Concurrently, Aβ production in the perforant path and levels of soluble Aβ and amyloid plaques in the hippocampus were significantly decreased. There was a positive correlation between the total APP protein level and NgR expression both in transgenic mice and in cultured cells, where the α-secretase and β-secretase cleavage products both changed with APP level in parallel. Finally, NgR might inhibit APP degradation through lysosome by Rho/Rho-associated protein kinases (ROCK) signaling pathway.ConclusionsOur findings demonstrate that perforant path NgR plays an important role in regulating APP/Aβ level and cognitive functions in AD transgenic mice, which might be related to the suppression of APP degradation by NgR. Our study suggests that NgR in the perforant path could be a potential target for modulating AD progression.