Role of Dlk1–Notch signaling in impaired neurogenesis and cognitive decline in chronic cerebral hypoperfusion

IF 3.3 Q3 BIOCHEMISTRY & MOLECULAR BIOLOGY

Biochemistry and Biophysics Reports Pub Date : 2026-06-01 Epub Date: 2026-05-28 DOI:10.1016/j.bbrep.2026.102650

Yoshiyuki Moriyama, Rena Hasegawa, Hikaru Endo, Sayaka Matsumura, Ryotaro Kaneko, Hideki Hayashi, Yui Iwatani, Norio Takagi

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引用次数: 0

Abstract

Vascular dementia (VaD) is characterized by chronic cerebral hypoperfusion, leading to cognitive decline. Impaired hippocampal neurogenesis is a crucial pathological feature of VaD. Delta-like 1 homolog (Dlk1)-Notch signaling may contribute to neural stem cell regulation, but the involvement of Dlk1-Notch signaling in impaired hippocampal neurogenesis during hypoperfusion is unclear. Here, we investigated the role of Dlk1 and Notch signaling in a mouse model of chronic cerebral hypoperfusion induced by bilateral carotid artery stenosis (BCAS). We found that BCAS increased Dlk1 levels in hippocampal tissue and cerebrospinal fluid, accompanied by elevated Notch intracellular domain (NICD) expression and reduced doublecortin (Dcx)-positive hippocampal cells. These changes were associated with impaired novel object recognition. In Neuro2a cells, hypoxia-mimetic treatment elevated NICD and extracellular Dlk1 and reduced cell viability, while pharmacological inhibition of Notch signaling partially rescued cell loss and attenuated these changes. These findings suggest that Dlk1-associated Notch activation correlates with impaired hippocampal neurogenesis and memory dysfunction under chronic hypoperfusion. Our results highlight a potential link between altered niche signaling and cognitive decline in VaD, providing a basis for further mechanistic investigation.

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Dlk1-Notch信号在慢性脑灌注不足患者神经发生受损和认知能力下降中的作用

血管性痴呆（VaD）的特点是慢性脑灌注不足，导致认知能力下降。海马神经发生受损是VaD的一个重要病理特征。delta -样1同源物(Dlk1)-Notch信号可能参与神经干细胞调控，但Dlk1-Notch信号是否参与低灌注时海马神经发生受损尚不清楚。在此，我们研究了Dlk1和Notch信号在双侧颈动脉狭窄（BCAS）引起的小鼠慢性脑灌注不足模型中的作用。我们发现BCAS增加了海马组织和脑脊液中的Dlk1水平，并伴有Notch细胞内结构域（NICD）表达升高和双皮质素（Dcx）阳性海马细胞减少。这些变化与新物体识别能力受损有关。在Neuro2a细胞中，模拟缺氧处理会升高NICD和细胞外Dlk1并降低细胞活力，而Notch信号的药物抑制部分挽救了细胞损失并减弱了这些变化。这些发现表明，dlk1相关的Notch激活与慢性低灌注下海马神经发生受损和记忆功能障碍有关。我们的研究结果强调了改变的生态位信号与VaD认知能力下降之间的潜在联系，为进一步的机制研究提供了基础。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Biochemistry and Biophysics Reports Biochemistry, Genetics and Molecular Biology-Biophysics

CiteScore

4.60

自引率

0.00%

发文量

191

审稿时长

59 days

期刊介绍： Open access, online only, peer-reviewed international journal in the Life Sciences, established in 2014 Biochemistry and Biophysics Reports (BB Reports) publishes original research in all aspects of Biochemistry, Biophysics and related areas like Molecular and Cell Biology. BB Reports welcomes solid though more preliminary, descriptive and small scale results if they have the potential to stimulate and/or contribute to future research, leading to new insights or hypothesis. Primary criteria for acceptance is that the work is original, scientifically and technically sound and provides valuable knowledge to life sciences research. We strongly believe all results deserve to be published and documented for the advancement of science. BB Reports specifically appreciates receiving reports on: Negative results, Replication studies, Reanalysis of previous datasets.