Elevated Levels of miR-144-3p Induce Cholinergic Degeneration by Impairing the Maturation of NGF in Alzheimer’s Disease
Cholinergic degeneration is one of the key pathological hallmarks of Alzheimer’s disease (AD), a condition that is characterized by synaptic disorders and memory impairments. Nerve growth factor (NGF) is secreted in brain regions that receive projections from the basal forebrain cholinergic neurons....
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Frontiers Media S.A.
2021-04-01
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| Series: | Frontiers in Cell and Developmental Biology |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fcell.2021.667412/full |
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| author | Lan-Ting Zhou Lan-Ting Zhou Juan Zhang Juan Zhang Lu Tan Lu Tan He-Zhou Huang He-Zhou Huang Yang Zhou Yang Zhou Zhi-Qiang Liu Zhi-Qiang Liu Youming Lu Ling-Qiang Zhu Ling-Qiang Zhu Chengye Yao Dan Liu |
| author_facet | Lan-Ting Zhou Lan-Ting Zhou Juan Zhang Juan Zhang Lu Tan Lu Tan He-Zhou Huang He-Zhou Huang Yang Zhou Yang Zhou Zhi-Qiang Liu Zhi-Qiang Liu Youming Lu Ling-Qiang Zhu Ling-Qiang Zhu Chengye Yao Dan Liu |
| author_sort | Lan-Ting Zhou |
| collection | DOAJ |
| description | Cholinergic degeneration is one of the key pathological hallmarks of Alzheimer’s disease (AD), a condition that is characterized by synaptic disorders and memory impairments. Nerve growth factor (NGF) is secreted in brain regions that receive projections from the basal forebrain cholinergic neurons. The trophic effects of NGF rely on the appropriate maturation of NGF from its precursor, proNGF. The ratio of proNGF/NGF is known to be increased in patients with AD; however, the mechanisms that underlie this observation have yet to be elucidated. Here, we demonstrated that levels of miR-144-3p are increased in the hippocampi and the medial prefrontal cortex of an APP/PS1 mouse model of AD. These mice also exhibited cholinergic degeneration (including the loss of cholinergic fibers, the repression of choline acetyltransferase (ChAT) activity, the reduction of cholinergic neurons, and an increased number of dystrophic neurites) and synaptic/memory deficits. The elevated expression of miR-144-3p specifically targets the mRNA of tissue plasminogen activator (tPA) and reduces the expression of tPA, thus resulting in the abnormal maturation of NGF. The administration of miR-144-3p fully replicated the cholinergic degeneration and synaptic/memory deficits observed in the APP/PS1 mice. The injection of an antagomir of miR-144-3p into the hippocampi partially rescued cholinergic degeneration and synaptic/memory impairments by restoring the levels of tPA protein and by correcting the ratio of proNGF/NGF. Collectively, our research revealed potential mechanisms for the disturbance of NGF maturation and cholinergic degeneration in AD and identified a potential therapeutic target for AD. |
| first_indexed | 2024-12-17T22:00:15Z |
| format | Article |
| id | doaj.art-5e529ce41d704f998cfc2fae16e4839b |
| institution | Directory Open Access Journal |
| issn | 2296-634X |
| language | English |
| last_indexed | 2024-12-17T22:00:15Z |
| publishDate | 2021-04-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Cell and Developmental Biology |
| spelling | doaj.art-5e529ce41d704f998cfc2fae16e4839b2022-12-21T21:31:00ZengFrontiers Media S.A.Frontiers in Cell and Developmental Biology2296-634X2021-04-01910.3389/fcell.2021.667412667412Elevated Levels of miR-144-3p Induce Cholinergic Degeneration by Impairing the Maturation of NGF in Alzheimer’s DiseaseLan-Ting Zhou0Lan-Ting Zhou1Juan Zhang2Juan Zhang3Lu Tan4Lu Tan5He-Zhou Huang6He-Zhou Huang7Yang Zhou8Yang Zhou9Zhi-Qiang Liu10Zhi-Qiang Liu11Youming Lu12Ling-Qiang Zhu13Ling-Qiang Zhu14Chengye Yao15Dan Liu16Department of Pathophysiology, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, ChinaCollaborative Innovation Center for Brain Science, The Institute of Brain Research, Huazhong University of Science and Technology, Wuhan, ChinaDepartment of Pathophysiology, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, ChinaCollaborative Innovation Center for Brain Science, The Institute of Brain Research, Huazhong University of Science and Technology, Wuhan, ChinaDepartment of Pathophysiology, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, ChinaCollaborative Innovation Center for Brain Science, The Institute of Brain Research, Huazhong University of Science and Technology, Wuhan, ChinaDepartment of Pathophysiology, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, ChinaCollaborative Innovation Center for Brain Science, The Institute of Brain Research, Huazhong University of Science and Technology, Wuhan, ChinaDepartment of Pathophysiology, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, ChinaCollaborative Innovation Center for Brain Science, The Institute of Brain Research, Huazhong University of Science and Technology, Wuhan, ChinaDepartment of Pathophysiology, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, ChinaCollaborative Innovation Center for Brain Science, The Institute of Brain Research, Huazhong University of Science and Technology, Wuhan, ChinaCollaborative Innovation Center for Brain Science, The Institute of Brain Research, Huazhong University of Science and Technology, Wuhan, ChinaDepartment of Pathophysiology, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, ChinaCollaborative Innovation Center for Brain Science, The Institute of Brain Research, Huazhong University of Science and Technology, Wuhan, ChinaDepartment of Neurology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, ChinaCollaborative Innovation Center for Brain Science, The Institute of Brain Research, Huazhong University of Science and Technology, Wuhan, ChinaCholinergic degeneration is one of the key pathological hallmarks of Alzheimer’s disease (AD), a condition that is characterized by synaptic disorders and memory impairments. Nerve growth factor (NGF) is secreted in brain regions that receive projections from the basal forebrain cholinergic neurons. The trophic effects of NGF rely on the appropriate maturation of NGF from its precursor, proNGF. The ratio of proNGF/NGF is known to be increased in patients with AD; however, the mechanisms that underlie this observation have yet to be elucidated. Here, we demonstrated that levels of miR-144-3p are increased in the hippocampi and the medial prefrontal cortex of an APP/PS1 mouse model of AD. These mice also exhibited cholinergic degeneration (including the loss of cholinergic fibers, the repression of choline acetyltransferase (ChAT) activity, the reduction of cholinergic neurons, and an increased number of dystrophic neurites) and synaptic/memory deficits. The elevated expression of miR-144-3p specifically targets the mRNA of tissue plasminogen activator (tPA) and reduces the expression of tPA, thus resulting in the abnormal maturation of NGF. The administration of miR-144-3p fully replicated the cholinergic degeneration and synaptic/memory deficits observed in the APP/PS1 mice. The injection of an antagomir of miR-144-3p into the hippocampi partially rescued cholinergic degeneration and synaptic/memory impairments by restoring the levels of tPA protein and by correcting the ratio of proNGF/NGF. Collectively, our research revealed potential mechanisms for the disturbance of NGF maturation and cholinergic degeneration in AD and identified a potential therapeutic target for AD.https://www.frontiersin.org/articles/10.3389/fcell.2021.667412/fullAlzheimer’s diseaseNGFmiR-144-3pcholinergic degenerationsynaptic disorder |
| spellingShingle | Lan-Ting Zhou Lan-Ting Zhou Juan Zhang Juan Zhang Lu Tan Lu Tan He-Zhou Huang He-Zhou Huang Yang Zhou Yang Zhou Zhi-Qiang Liu Zhi-Qiang Liu Youming Lu Ling-Qiang Zhu Ling-Qiang Zhu Chengye Yao Dan Liu Elevated Levels of miR-144-3p Induce Cholinergic Degeneration by Impairing the Maturation of NGF in Alzheimer’s Disease Frontiers in Cell and Developmental Biology Alzheimer’s disease NGF miR-144-3p cholinergic degeneration synaptic disorder |
| title | Elevated Levels of miR-144-3p Induce Cholinergic Degeneration by Impairing the Maturation of NGF in Alzheimer’s Disease |
| title_full | Elevated Levels of miR-144-3p Induce Cholinergic Degeneration by Impairing the Maturation of NGF in Alzheimer’s Disease |
| title_fullStr | Elevated Levels of miR-144-3p Induce Cholinergic Degeneration by Impairing the Maturation of NGF in Alzheimer’s Disease |
| title_full_unstemmed | Elevated Levels of miR-144-3p Induce Cholinergic Degeneration by Impairing the Maturation of NGF in Alzheimer’s Disease |
| title_short | Elevated Levels of miR-144-3p Induce Cholinergic Degeneration by Impairing the Maturation of NGF in Alzheimer’s Disease |
| title_sort | elevated levels of mir 144 3p induce cholinergic degeneration by impairing the maturation of ngf in alzheimer s disease |
| topic | Alzheimer’s disease NGF miR-144-3p cholinergic degeneration synaptic disorder |
| url | https://www.frontiersin.org/articles/10.3389/fcell.2021.667412/full |
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