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.
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This post is Copyright: Chen Zhang,
Qingqing Jia,
Longhong Zhu,
Junqi Hou,
Xiang Wang,
Dandan Li,
Jiawei Zhang,
Yiran Zhang,
Su Yang,
Zhuchi Tu,
Xiao‐Xin Yan,
Weili Yang,
Shihua Li,
Xiao‐Jiang Li,
Peng Yin | July 17, 2024