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

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Title: Agomirs upregulating carboxypeptidase E expression rescue hippocampal neurogenesis and memory deficits in Alzheimer’s disease
Authors: Dongfang Jiang, Hongmei Liu, Tingting Li, Song Zhao, Keyan Yang, Fuwen Yao, Bo Zhou, Haiping Feng, Sijia Wang, Jiaqi Shen, Jinglan Tang, Yu-Xin Zhang, Yun Wang, Caixia Guo, Tie-Shan Tang
Source: Translational Neurodegeneration, Vol 13, Iss 1, Pp 1-21 (2024)
Publisher Information: BMC, 2024.
Publication Year: 2024
Collection: LCC:Neurology. Diseases of the nervous system
Subject Terms: Carboxypeptidase E, Adult hippocampal neurogenesis, Agomir, BDNF, Alzheimer’s disease, Memory deficit, Neurology. Diseases of the nervous system, RC346-429
More Details: Abstract Background Adult 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). Methods In 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. Results Restoration 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. Conclusions CPE 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.
Document Type: article
File Description: electronic resource
Language: English
ISSN: 2047-9158
Relation: https://doaj.org/toc/2047-9158
DOI: 10.1186/s40035-024-00414-z
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  Data: Agomirs upregulating carboxypeptidase E expression rescue hippocampal neurogenesis and memory deficits in Alzheimer’s disease
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  Data: <searchLink fieldCode="AR" term="%22Dongfang+Jiang%22">Dongfang Jiang</searchLink><br /><searchLink fieldCode="AR" term="%22Hongmei+Liu%22">Hongmei Liu</searchLink><br /><searchLink fieldCode="AR" term="%22Tingting+Li%22">Tingting Li</searchLink><br /><searchLink fieldCode="AR" term="%22Song+Zhao%22">Song Zhao</searchLink><br /><searchLink fieldCode="AR" term="%22Keyan+Yang%22">Keyan Yang</searchLink><br /><searchLink fieldCode="AR" term="%22Fuwen+Yao%22">Fuwen Yao</searchLink><br /><searchLink fieldCode="AR" term="%22Bo+Zhou%22">Bo Zhou</searchLink><br /><searchLink fieldCode="AR" term="%22Haiping+Feng%22">Haiping Feng</searchLink><br /><searchLink fieldCode="AR" term="%22Sijia+Wang%22">Sijia Wang</searchLink><br /><searchLink fieldCode="AR" term="%22Jiaqi+Shen%22">Jiaqi Shen</searchLink><br /><searchLink fieldCode="AR" term="%22Jinglan+Tang%22">Jinglan Tang</searchLink><br /><searchLink fieldCode="AR" term="%22Yu-Xin+Zhang%22">Yu-Xin Zhang</searchLink><br /><searchLink fieldCode="AR" term="%22Yun+Wang%22">Yun Wang</searchLink><br /><searchLink fieldCode="AR" term="%22Caixia+Guo%22">Caixia Guo</searchLink><br /><searchLink fieldCode="AR" term="%22Tie-Shan+Tang%22">Tie-Shan Tang</searchLink>
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  Data: Translational Neurodegeneration, Vol 13, Iss 1, Pp 1-21 (2024)
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  Data: Abstract Background Adult 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). Methods In 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. Results Restoration 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. Conclusions CPE 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.
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      – SubjectFull: Carboxypeptidase E
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