Aβ-induced degradation of BMAL1 and CBP leads to circadian rhythm disruption in Alzheimer’s...

Aβ-induced degradation of BMAL1 and CBP leads to circadian rhythm disruption in Alzheimer’s disease

Molecular Neurodegeneration(19 March 2015 ； IF= 6.563 ； PMID ：

25888034)王宁2015.10.8

IMI CONFIDENTIAL www.xianimi.com

Background

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Aβ, Amyloid-beta

SCN, Suprachiasmatic nucleus

CBP, Creb-binding protein

Per2, Period circadian protein homolog 2

BMAL1, Aryl hydrocarbon receptor nuclear translocator-lik

e

生理节律相关的蛋白，时钟基因：


Materials and Methods

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Animal : 5XFAD mice (APP/PSEN1) AD 小鼠 APP K670N/M671L+I716V+V717I

PSEN1 M146L+L286V

Cell: HT22 mouse hippocampal cells,

Cos7 monkey kidney cells

Methods: Behavioral assay, Immunocytochemistry,

Western blot, real-time PCR, Immunoprecipitation,

Luciferase reporter assays, BiFC assay, ELISA.


Results

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1. Abnormal circadian behavior in 5XFAD mice


Results

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1. Abnormal circadian behavior in 5XFAD mice


Results

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2. The expression of molecular circadian clock genes, Bmal1, Cbp and Per2, are impaired in 5XFAD mice

与对照小鼠相比， AD小鼠SCN 中 Bmal1, Per2, Cbp mRNA水平明显发生了改变。


Results

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Results

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与对照小鼠相比， AD小鼠SCN 中 Bmal1, Per2, Cbp 蛋白水平并不呈现振荡表达。


Results

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3. Aβ induces the degradation of BMAL1 and CBP

Aβ 作用之后，细胞内 BMAL1 和 CBP 蛋白水平的振荡表达被减弱。


Results

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Results

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Aβ 作用 24 h 之后，细胞内 BMAL1 和 CBP 蛋白水平的振荡表达被减弱。


Results

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Aβ 作用 24 h 之后，细胞内 BMAL1 和 CBP 蛋白的相互作用被减弱。


Results

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4. The degradation of BMAL1 by Aβ involves the sumoylation of BMAL1

随着 Aβ 作用时间的增长，细胞内 BMAL1 蛋白的水平逐渐降低。


Results

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Aβ 作用导致细胞内 BMAL1 蛋白的泛素化降解。


Results

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沉默类泛素蛋白之后，减轻了 Aβ 诱导的 BMAL1 降解。


Results

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BMAL1 突变体显著抑制了 Aβ 导致的 BMAL1 降解。


Results

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5. Aβ induces N-Cadherin CTF2-mediated degradation of CBP through the cleavage of N-Cadherin by γ-secretase

N-Cad 的过表达抑制了CBP 的水平。 Aβ 提高了N-Cad CTF 的水平。


Results

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5. Aβ induces N-Cadherin CTF2-mediated degradation of CBP through the cleavage of N-Cadherin by γ-secretase

γ 分泌酶抑制剂

Aβ 对 CBP 的降解作用是通过 γ 分泌酶对 N-Cad 的裂解来实现的。


Results

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6. Aβ modulates the expression of Per2 mRNA through Aβ-mediated degradation of BMAL1 and CBP

Aβ 作用之后，细胞内 Per2 mRNA 水平显著变化。


Results

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Results

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Aβ 对 Per2 的降解是通过对 BMAL1 和 CBP 的降解实现的。


Results

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Results

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Results

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IMI CONFIDENTIAL

Conclusions

1. Aβ may affect circadian rhythm in 5XFAD mice

2. 5XFAD mice have impairments in the regulation of circadian clock genes

3. Aβ impacts on the metabolic stabilities of BMAL1 and CBP proteins.

4. Aβ-induced BMAL1 degradation is due to the sumoylation of BMAL1

5. The cleavage of N-Cadherin by γ-secretase is the molecularmechanism underlying Aβ-induced degradation of CBP.

6. Aβ modulates the expression of Per2 mRNA through Aβ- mediated degradation of BMAL1 and CBP.

IMI CONFIDENTIAL

Conclusions

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Aβ-induced degradation of BMAL1 and CBP leads to circadian rhythm disruption in Alzheimer’s...

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