Agomirs upregulating carboxypeptidase E expression rescue hippocampal neurogenesis and memory deficits in Alzheimer's disease

被引：8

作者：

Jiang, Dongfang ^{[1
,4
]}

Liu, Hongmei ^{[1
,3
]}

Li, Tingting ^{[1
,4
]}

Zhao, Song ^{[1
,4
]}

Yang, Keyan ^{[1
,4
]}

Yao, Fuwen ^{[2
,4
]}

Zhou, Bo ^{[2
]}

Feng, Haiping ^{[1
,4
]}

Wang, Sijia ^{[1
,4
]}

Shen, Jiaqi ^{[1
,4
]}

Tang, Jinglan ^{[1
,5
]}

Zhang, Yu-Xin ^{[1
,4
]}

Wang, Yun ^{[1
]}

Guo, Caixia ^{[2
,4
]}

Tang, Tie-Shan ^{[1
,3
,4
]}

机构：

[1] Chinese Acad Sci, Inst Zool, Key Lab Organ Regenerat & Reconstruct, State Key Lab Membrane Biol, Beijing 100101, Peoples R China

[2] Chinese Acad Sci, Beijing Inst Genom, China Natl Ctr Bioinformat, Beijing 100101, Peoples R China

[3] Beijing Inst Stem Cell & Regenerat Med, Beijing 100101, Peoples R China

[4] Univ Chinese Acad Sci, Chinese Acad Sci, Beijing 100101, Peoples R China

[5] Univ Calif San Diego, Dept Psychol, La Jolla, CA 92093 USA

来源：

TRANSLATIONAL NEURODEGENERATION | 2024年 / 13卷 / 01期

基金：

中国国家自然科学基金;

关键词：

Carboxypeptidase E; Adult hippocampal neurogenesis; Agomir; BDNF; Alzheimer's disease; Memory deficit; Intranasal instillation; NEUROTROPHIC FACTOR; AMYLOID PLAQUES; HUMAN BRAIN; BDNF; PROLIFERATION; PROTEIN; ENDOCRINE; MICROGLIA; SECRETION; DELIVERY;

D O I：

10.1186/s40035-024-00414-z

中图分类号：

Q189 [神经科学];

学科分类号：

071006 ;

摘要：

BackgroundAdult neurogenesis occurs in the subventricular zone (SVZ) and the subgranular zone of the dentate gyrus in the hippocampus. The neuronal stem cells in these two neurogenic niches respond differently to various physiological and pathological stimuli. Recently, we have found that the decrement of carboxypeptidase E (CPE) with aging impairs the maturation of brain-derived neurotrophic factor (BDNF) and neurogenesis in the SVZ. However, it remains unknown whether these events occur in the hippocampus, and what the role of CPE is in the adult hippocampal neurogenesis in the context of Alzheimer's disease (AD).MethodsIn vivo screening was performed to search for miRNA mimics capable of upregulating CPE expression and promoting neurogenesis in both neurogenic niches. Among these, two agomirs were further assessed for their effects on hippocampal neurogenesis in the context of AD. We also explored whether these two agomirs could ameliorate behavioral symptoms and AD pathology in mice, using direct intracerebroventricular injection or by non-invasive intranasal instillation.ResultsRestoration of CPE expression in the hippocampus improved BDNF maturation and boosted adult hippocampal neurogenesis. By screening the miRNA mimics targeting the 5'UTR region of Cpe gene, we developed two agomirs that were capable of upregulating CPE expression. The two agomirs significantly rescued adult neurogenesis and cognition, showing multiple beneficial effects against the AD-associated pathologies in APP/PS1 mice. Of note, noninvasive approach via intranasal delivery of these agomirs improved the behavioral and neurocognitive functions of APP/PS1 mice.ConclusionsCPE may regulate adult hippocampal neurogenesis via the CPE-BDNF-TrkB signaling pathway. This study supports the prospect of developing miRNA agomirs targeting CPE as biopharmaceuticals to counteract aging- and disease-related neurological decline in human brains.

引用

页数：21

共 67 条

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