Human microRNA (miR-20b-5p) modulates Alzheimer’s disease pathways and neuronal function, and a specific polymorphism close to the MIR20B gene influences Alzheimer’s biomarkers

Ruizhi Wang; Nipun Chopra; Kwangsik Nho; Bryan Maloney; Alexander G. Obukhov; Peter T. Nelson; Scott E. Counts; Debomoy K. Lahiri

doi:10.1038/s41380-021-01351-3

Human microRNA (miR-20b-5p) modulates Alzheimer’s disease pathways and neuronal function, and a specific polymorphism close to the MIR20B gene influences Alzheimer’s biomarkers

Ruizhi Wang, Nipun Chopra, Kwangsik Nho, Bryan Maloney, Alexander G. Obukhov, Peter T. Nelson, Scott E. Counts, Debomoy K. Lahiri

Research output: Contribution to journal › Article › peer-review

52 Scopus citations

Abstract

Alzheimer’s disease (AD) is a progressive neurodegenerative disorder with loss of cognitive, executive, and other mental functions, and is the most common form of age-related dementia. Amyloid-β peptide (Aβ) contributes to the etiology and progression of the disease. Aβ is derived from the amyloid-β precursor protein (APP). Multiple microRNA (miRNA) species are also implicated in AD. We report that human hsa-miR20b-5p (miR-20b), produced from the MIR20B gene on Chromosome X, may play complex roles in AD pathogenesis, including Aβ regulation. Specifically, miR-20b-5p miRNA levels were altered in association with disease progression in three regions of the human brain: temporal neocortex, cerebellum, and posterior cingulate cortex. In cultured human neuronal cells, miR-20b-5p treatment interfered with calcium homeostasis, neurite outgrowth, and branchpoints. A single-nucleotide polymorphism (SNP) upstream of the MIR20B gene (rs13897515) associated with differences in levels of cerebrospinal fluid (CSF) Aβ_1-42 and thickness of the entorhinal cortex. We located a miR-20b-5p binding site in the APP mRNA 3′-untranslated region (UTR), and treatment with miR-20b-5p reduced APP mRNA and protein levels. Network analysis of protein-protein interactions and gene coexpression revealed other important potential miR-20b-5p targets among AD-related proteins/genes. MiR-20b-5p, a miRNA that downregulated APP, was paradoxically associated with an increased risk for AD. However, miR-20b-5p also reduced, and the blockade of APP by siRNA likewise reduced calcium influx. As APP plays vital roles in neuronal health and does not exist solely to be the source of “pathogenic” Aβ, the molecular etiology of AD is likely to not just be a disease of “excess” but a disruption of delicate homeostasis.

Original language	English
Pages (from-to)	1256-1273
Number of pages	18
Journal	Molecular Psychiatry
Volume	27
Issue number	2
DOIs	https://doi.org/10.1038/s41380-021-01351-3
State	Published - Feb 2022

Bibliographical note

Publisher Copyright:
© 2021, The Author(s).

Funding

The authors would like to thank Drs Bernardino Ghetti, Baindu Bayon, Bruce Lamb, Justin Long, Balmiki Ray, Andrew Saykin and Fletcher White for their advice, and John Beck for technical assistance. We further thank Dr. Eliott Mufson for his support and Dr. Xiao-Ming Xu for the IncuCyte Zoom. We sincerely thank Drs. Ian Glass and Diana O?Day and also acknowledge the Birth Defects Research Laboratory at University of Washington, Seattle. Further, the authors appreciate support from the Research Education and Neuroimaging Cores of the Indiana Alzheimer?s Disease Research Center (IADRC). DKL has received grant supports from NIH-NIA (R01AG051086, R21AG074539, R21AG056007?and?R56AG072810). KN has received grant supports from NIH (R01LM012535, R03AG054936, R03AG063250). Authors are grateful for support from the NIA IADRC (P30AG010133). SEC receives grant support from NIH grants P01AG014449 (with DKL), P30 AG072931, and R01AG060731. Some data used in preparation of this article were obtained from the ADNI database (adni.loni.usc.edu). As such, investigators within ADNI contributed to the design and implementation of ADNI and/or provided data but did not participate in analysis or writing of this report. A complete listing of ADNI investigators can be found at: http://adni.loni.usc.edu/wp-content/uploads/how_to_apply/ADNI_Acknowledgement_List.pdf. ADNI-associated data collection and sharing for this project was funded by the ADNI (National Institutes of Health Grant U01 AG024904) and DOD ADNI (Department of Defense award number W81XWH-12-2-0012). ADNI is funded by the National Institute on Aging, the National Institute of Biomedical Imaging and Bioengineering, and through generous contributions from the following: AbbVie, Alzheimer?s Association; Alzheimer?s Drug Discovery Foundation; Araclon Biotech; BioClinica, Inc.; Biogen; Bristol-Myers Squibb Company; CereSpir, Inc.; Cogstate; Eisai Inc.; Elan Pharmaceuticals, Inc.; Eli Lilly and Company; EuroImmun; F. Hoffmann-La Roche Ltd and its affiliated company Genentech, Inc.; Fujirebio; GE Healthcare; IXICO Ltd.; Janssen Alzheimer Immunotherapy Research & Development, LLC.; Johnson & Johnson Pharmaceutical Research & Development LLC.; Lumosity; Lundbeck; Merck & Co., Inc.; Meso Scale Diagnostics, LLC.; NeuroRx Research; Neurotrack Technologies; Novartis Pharmaceuticals Corporation; Pfizer Inc.; Piramal Imaging; Servier; Takeda Pharmaceutical Company; and Transition Therapeutics. The Canadian Institutes of Health Research is providing funds to support ADNI clinical sites in Canada. Private sector contributions are facilitated by the Foundation for the National Institutes of Health (www.fnih.org). The grantee organization is the Northern California Institute for Research and Education, and the study is coordinated by the Alzheimer?s Therapeutic Research Institute at the University of Southern California. ADNI data are disseminated by the Laboratory for Neuro Imaging at the University of Southern California. The authors would like to thank Drs Bernardino Ghetti, Baindu Bayon, Bruce Lamb, Justin Long, Balmiki Ray, Andrew Saykin and Fletcher White for their advice, and John Beck for technical assistance. We further thank Dr. Eliott Mufson for his support and Dr. Xiao-Ming Xu for the IncuCyte Zoom. We sincerely thank Drs. Ian Glass and Diana O’Day and also acknowledge the Birth Defects Research Laboratory at University of Washington, Seattle. Further, the authors appreciate support from the Research Education and Neuroimaging Cores of the Indiana Alzheimer’s Disease Research Center (IADRC). DKL has received grant supports from NIH-NIA (R01AG051086, R21AG074539, R21AG056007 and R56AG072810). KN has received grant supports from NIH (R01LM012535, R03AG054936, R03AG063250). Authors are grateful for support from the NIA IADRC (P30AG010133). SEC receives grant support from NIH grants P01AG014449 (with DKL), P30 AG072931, and R01AG060731. Some data used in preparation of this article were obtained from the ADNI database (adni.loni.usc.edu). As such, investigators within ADNI contributed to the design and implementation of ADNI and/or provided data but did not participate in analysis or writing of this report. A complete listing of ADNI investigators can be found at: http://adni.loni.usc.edu/wp-content/uploads/how_to_apply/ADNI_Acknowledgement_List.pdf. ADNI-associated data collection and sharing for this project was funded by the ADNI (National Institutes of Health Grant U01 AG024904) and DOD ADNI (Department of Defense award number W81XWH-12-2-0012). ADNI is funded by the National Institute on Aging, the National Institute of Biomedical Imaging and Bioengineering, and through generous contributions from the following: AbbVie, Alzheimer’s Association; Alzheimer’s Drug Discovery Foundation; Araclon Biotech; BioClinica, Inc.; Biogen; Bristol-Myers Squibb Company; CereSpir, Inc.; Cogstate; Eisai Inc.; Elan Pharmaceuticals, Inc.; Eli Lilly and Company; EuroImmun; F. Hoffmann-La Roche Ltd and its affiliated company Genentech, Inc.; Fujirebio; GE Healthcare; IXICO Ltd.; Janssen Alzheimer Immunotherapy Research & Development, LLC.; Johnson & Johnson Pharmaceutical Research & Development LLC.; Lumosity; Lundbeck; Merck & Co., Inc.; Meso Scale Diagnostics, LLC.; NeuroRx Research; Neurotrack Technologies; Novartis Pharmaceuticals Corporation; Pfizer Inc.; Piramal Imaging; Servier; Takeda Pharmaceutical Company; and Transition Therapeutics. The Canadian Institutes of Health Research is providing funds to support ADNI clinical sites in Canada. Private sector contributions are facilitated by the Foundation for the National Institutes of Health (www.fnih.org). The grantee organization is the Northern California Institute for Research and Education, and the study is coordinated by the Alzheimer’s Therapeutic Research Institute at the University of Southern California. ADNI data are disseminated by the Laboratory for Neuro Imaging at the University of Southern California.

Funders	Funder number
Northern California Institute for Research and Education
University of Southern California
National Institute of Biomedical Imaging and Bioengineering
DoD Alzheimer's Disease Neuroimaging Initiative
Indiana Alzheimer?s Disease Research Center
The George Washington University
DOD ADNI
National Institute on Aging
NIA/NIH	R21AG056007?and?R56AG072810, R21AG074539, R56AG072810, R01AG051086, R21AG056007
National Institutes of Health (NIH)	R01LM012535, R03AG054936, R03AG063250, U01 AG024904
National Institutes of Health (NIH)
NIA IADRC	P30 AG072931, P30AG010133, R01AG060731, P01AG014449
U.S. Department of Defense	W81XWH-12-2-0012
U.S. Department of Defense

ASJC Scopus subject areas

Molecular Biology
Cellular and Molecular Neuroscience
Psychiatry and Mental health

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1038/s41380-021-01351-3

Cite this

Wang, R., Chopra, N., Nho, K., Maloney, B., Obukhov, A. G., Nelson, P. T., Counts, S. E., & Lahiri, D. K. (2022). Human microRNA (miR-20b-5p) modulates Alzheimer’s disease pathways and neuronal function, and a specific polymorphism close to the MIR20B gene influences Alzheimer’s biomarkers. Molecular Psychiatry, 27(2), 1256-1273. https://doi.org/10.1038/s41380-021-01351-3

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title = "Human microRNA (miR-20b-5p) modulates Alzheimer{\textquoteright}s disease pathways and neuronal function, and a specific polymorphism close to the MIR20B gene influences Alzheimer{\textquoteright}s biomarkers",

abstract = "Alzheimer{\textquoteright}s disease (AD) is a progressive neurodegenerative disorder with loss of cognitive, executive, and other mental functions, and is the most common form of age-related dementia. Amyloid-β peptide (Aβ) contributes to the etiology and progression of the disease. Aβ is derived from the amyloid-β precursor protein (APP). Multiple microRNA (miRNA) species are also implicated in AD. We report that human hsa-miR20b-5p (miR-20b), produced from the MIR20B gene on Chromosome X, may play complex roles in AD pathogenesis, including Aβ regulation. Specifically, miR-20b-5p miRNA levels were altered in association with disease progression in three regions of the human brain: temporal neocortex, cerebellum, and posterior cingulate cortex. In cultured human neuronal cells, miR-20b-5p treatment interfered with calcium homeostasis, neurite outgrowth, and branchpoints. A single-nucleotide polymorphism (SNP) upstream of the MIR20B gene (rs13897515) associated with differences in levels of cerebrospinal fluid (CSF) Aβ1-42 and thickness of the entorhinal cortex. We located a miR-20b-5p binding site in the APP mRNA 3′-untranslated region (UTR), and treatment with miR-20b-5p reduced APP mRNA and protein levels. Network analysis of protein-protein interactions and gene coexpression revealed other important potential miR-20b-5p targets among AD-related proteins/genes. MiR-20b-5p, a miRNA that downregulated APP, was paradoxically associated with an increased risk for AD. However, miR-20b-5p also reduced, and the blockade of APP by siRNA likewise reduced calcium influx. As APP plays vital roles in neuronal health and does not exist solely to be the source of “pathogenic” Aβ, the molecular etiology of AD is likely to not just be a disease of “excess” but a disruption of delicate homeostasis.",

author = "Ruizhi Wang and Nipun Chopra and Kwangsik Nho and Bryan Maloney and Obukhov, \{Alexander G.\} and Nelson, \{Peter T.\} and Counts, \{Scott E.\} and Lahiri, \{Debomoy K.\}",

note = "Publisher Copyright: {\textcopyright} 2021, The Author(s).",

year = "2022",

month = feb,

doi = "10.1038/s41380-021-01351-3",

language = "English",

volume = "27",

pages = "1256--1273",

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Wang, R, Chopra, N, Nho, K, Maloney, B, Obukhov, AG, Nelson, PT, Counts, SE & Lahiri, DK 2022, 'Human microRNA (miR-20b-5p) modulates Alzheimer’s disease pathways and neuronal function, and a specific polymorphism close to the MIR20B gene influences Alzheimer’s biomarkers', Molecular Psychiatry, vol. 27, no. 2, pp. 1256-1273. https://doi.org/10.1038/s41380-021-01351-3

TY - JOUR

T1 - Human microRNA (miR-20b-5p) modulates Alzheimer’s disease pathways and neuronal function, and a specific polymorphism close to the MIR20B gene influences Alzheimer’s biomarkers

AU - Wang, Ruizhi

AU - Chopra, Nipun

AU - Nho, Kwangsik

AU - Maloney, Bryan

AU - Obukhov, Alexander G.

AU - Nelson, Peter T.

AU - Counts, Scott E.

AU - Lahiri, Debomoy K.

PY - 2022/2

Y1 - 2022/2

N2 - Alzheimer’s disease (AD) is a progressive neurodegenerative disorder with loss of cognitive, executive, and other mental functions, and is the most common form of age-related dementia. Amyloid-β peptide (Aβ) contributes to the etiology and progression of the disease. Aβ is derived from the amyloid-β precursor protein (APP). Multiple microRNA (miRNA) species are also implicated in AD. We report that human hsa-miR20b-5p (miR-20b), produced from the MIR20B gene on Chromosome X, may play complex roles in AD pathogenesis, including Aβ regulation. Specifically, miR-20b-5p miRNA levels were altered in association with disease progression in three regions of the human brain: temporal neocortex, cerebellum, and posterior cingulate cortex. In cultured human neuronal cells, miR-20b-5p treatment interfered with calcium homeostasis, neurite outgrowth, and branchpoints. A single-nucleotide polymorphism (SNP) upstream of the MIR20B gene (rs13897515) associated with differences in levels of cerebrospinal fluid (CSF) Aβ1-42 and thickness of the entorhinal cortex. We located a miR-20b-5p binding site in the APP mRNA 3′-untranslated region (UTR), and treatment with miR-20b-5p reduced APP mRNA and protein levels. Network analysis of protein-protein interactions and gene coexpression revealed other important potential miR-20b-5p targets among AD-related proteins/genes. MiR-20b-5p, a miRNA that downregulated APP, was paradoxically associated with an increased risk for AD. However, miR-20b-5p also reduced, and the blockade of APP by siRNA likewise reduced calcium influx. As APP plays vital roles in neuronal health and does not exist solely to be the source of “pathogenic” Aβ, the molecular etiology of AD is likely to not just be a disease of “excess” but a disruption of delicate homeostasis.

AB - Alzheimer’s disease (AD) is a progressive neurodegenerative disorder with loss of cognitive, executive, and other mental functions, and is the most common form of age-related dementia. Amyloid-β peptide (Aβ) contributes to the etiology and progression of the disease. Aβ is derived from the amyloid-β precursor protein (APP). Multiple microRNA (miRNA) species are also implicated in AD. We report that human hsa-miR20b-5p (miR-20b), produced from the MIR20B gene on Chromosome X, may play complex roles in AD pathogenesis, including Aβ regulation. Specifically, miR-20b-5p miRNA levels were altered in association with disease progression in three regions of the human brain: temporal neocortex, cerebellum, and posterior cingulate cortex. In cultured human neuronal cells, miR-20b-5p treatment interfered with calcium homeostasis, neurite outgrowth, and branchpoints. A single-nucleotide polymorphism (SNP) upstream of the MIR20B gene (rs13897515) associated with differences in levels of cerebrospinal fluid (CSF) Aβ1-42 and thickness of the entorhinal cortex. We located a miR-20b-5p binding site in the APP mRNA 3′-untranslated region (UTR), and treatment with miR-20b-5p reduced APP mRNA and protein levels. Network analysis of protein-protein interactions and gene coexpression revealed other important potential miR-20b-5p targets among AD-related proteins/genes. MiR-20b-5p, a miRNA that downregulated APP, was paradoxically associated with an increased risk for AD. However, miR-20b-5p also reduced, and the blockade of APP by siRNA likewise reduced calcium influx. As APP plays vital roles in neuronal health and does not exist solely to be the source of “pathogenic” Aβ, the molecular etiology of AD is likely to not just be a disease of “excess” but a disruption of delicate homeostasis.

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Human microRNA (miR-20b-5p) modulates Alzheimer’s disease pathways and neuronal function, and a specific polymorphism close to the MIR20B gene influences Alzheimer’s biomarkers

Abstract

Bibliographical note

Funding

ASJC Scopus subject areas

UN SDGs

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