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抑制 UBE2N 通过清除淀粉样β缓解阿尔茨海默病病理。

Suppressing UBE2N ameliorates Alzheimer's disease pathology through the clearance of amyloid beta.

机构信息

State Key Laboratory of Bioactive Molecules and Druggability Assessment, Guangdong Key Laboratory of Non-human Primate Research, Guangdong-Hongkong-Macau Institute of CNS Regeneration, Jinan University, Guangzhou, China.

Department of Anatomy and Neurobiology, Xiangya School of Medicine, Central South University, Changsha, China.

出版信息

Alzheimers Dement. 2024 Sep;20(9):6287-6304. doi: 10.1002/alz.14122. Epub 2024 Jul 17.

DOI:10.1002/alz.14122
PMID:39015037
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC11497675/
Abstract

INTRODUCTION

Aging is one of the risk factors for the early onset of Alzheimer's disease (AD). We previously discovered that the age-dependent increase in Ubiquitin Conjugating Enzyme E2 N (UBE2N) plays a role in the accumulation of misfolded proteins through K63 ubiquitination, which has been linked to AD pathogenesis. However, the impact of UBE2N on amyloid pathology and clearance has remained unknown.

RESULTS

We observed the elevated UBE2N during the amyloid beta (Aβ) generation in the brains of 5×FAD, APP/PS1 mice, and patients with AD, in comparison to healthy individuals. UBE2N overexpression exacerbated amyloid deposition in 5×FAD mice and senescent monkeys, whereas knocking down UBE2N via CRISPR/Cas9 reduced Aβ generation and cognitive deficiency. Moreover, pharmacological inhibition of UBE2N ameliorated Aβ pathology and subsequent transcript defects in 5×FAD mice.

DISCUSSION

We have discovered that age-dependent expression of UBE2N is a critical regulator of AD pathology. Our findings suggest that UBE2N could serve as a potential pharmacological target for the advancement of AD therapeutics.

HIGHLIGHTS

Ubiquitin Conjugating Enzyme E2 N (UBE2N) level was elevated during amyloid beta (Aβ) deposition in AD mouse and patients' brains. UBE2N exacerbated Aβ generation in the AD mouse and senescent monkey. Drug inhibition of UBE2N ameliorated Aβ pathology and cognitive deficiency.

摘要

简介

衰老 是阿尔茨海默病（AD） 早发的一个风险因素。我们之前发现，泛素结合酶 E2 N（UBE2N） 的年龄依赖性增加通过 K63 泛素化在错误折叠蛋白的积累中发挥作用，这与 AD 的发病机制有关。然而，UBE2N 对淀粉样蛋白病理和清除的影响仍不清楚。

结果

与健康个体相比，我们在 5×FAD、APP/PS1 小鼠和 AD 患者的大脑中观察到淀粉样蛋白β（Aβ）生成过程中 UBE2N 的升高。UBE2N 的过表达加剧了 5×FAD 小鼠的淀粉样蛋白沉积，而通过 CRISPR/Cas9 敲低 UBE2N 则减少了 Aβ的生成和认知缺陷。此外，UBE2N 的药理学抑制改善了 5×FAD 小鼠的 Aβ病理学和随后的转录缺陷。

讨论

我们发现 UBE2N 的年龄依赖性表达是 AD 病理的一个关键调节因子。我们的研究结果表明，UBE2N 可能成为 AD 治疗进展的潜在药物靶点。

重点

在 AD 小鼠和患者大脑的淀粉样蛋白沉积期间，泛素结合酶 E2 N（UBE2N）的水平升高。UBE2N 加剧了 AD 小鼠和衰老猴子的 Aβ生成。UBE2N 的药物抑制改善了 Aβ病理学和认知缺陷。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/aafc/11497675/7dcde79a6dbf/ALZ-20-6287-g006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/aafc/11497675/eca44dfa3c62/ALZ-20-6287-g001.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/aafc/11497675/74de43ed9778/ALZ-20-6287-g007.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/aafc/11497675/9c6e9b7c0504/ALZ-20-6287-g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/aafc/11497675/782162efd33e/ALZ-20-6287-g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/aafc/11497675/f3c483068f70/ALZ-20-6287-g005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/aafc/11497675/4aa6fb5d32a9/ALZ-20-6287-g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/aafc/11497675/7dcde79a6dbf/ALZ-20-6287-g006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/aafc/11497675/eca44dfa3c62/ALZ-20-6287-g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/aafc/11497675/4cb26f201817/ALZ-20-6287-g008.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/aafc/11497675/74de43ed9778/ALZ-20-6287-g007.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/aafc/11497675/9c6e9b7c0504/ALZ-20-6287-g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/aafc/11497675/782162efd33e/ALZ-20-6287-g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/aafc/11497675/f3c483068f70/ALZ-20-6287-g005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/aafc/11497675/4aa6fb5d32a9/ALZ-20-6287-g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/aafc/11497675/7dcde79a6dbf/ALZ-20-6287-g006.jpg

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