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Deregulation of neuronal miRNAs induced by amyloid-β or TAU pathology.
Mol Neurodegener. 2018 10 12; 13(1):54.MN

Abstract

BACKGROUND

Despite diverging levels of amyloid-β (Aβ) and TAU pathology, different mouse models, as well as sporadic AD patients show predictable patterns of episodic memory loss. MicroRNA (miRNA) deregulation is well established in AD brain but it is unclear whether Aβ or TAU pathology drives those alterations and whether miRNA changes contribute to cognitive decline.

METHODS

miRNAseq was performed on cognitively intact (4 months) and impaired (10 months) male APPtg (APPswe/PS1L166P) and TAUtg (THY-Tau22) mice and their wild-type littermates (APPwt and TAUwt). We analyzed the hippocampi of 12 mice per experimental group (n = 96 in total), and employed a 2-way linear model to extract differentially expressed miRNAs. Results were confirmed by qPCR in a separate cohort of 4 M and 10 M APPtg and APPwt mice (n = 7-9 per group) and in human sporadic AD and non-demented control brain. Fluorescent in situ hybridization identified their cellular expression. Functional annotation of predicted targets was performed using GO enrichment. Behavior of wild-type mice was assessed after intracerebroventricular infusion of miRNA mimics.

RESULTS

Six miRNAs (miR-10a-5p, miR-142a-5p, miR-146a-5p, miR-155-5p, miR-211-5p, miR-455-5p) are commonly upregulated between APPtg and TAUtg mice, and four of these (miR-142a-5p, miR-146a-5p, miR-155-5p and miR-455-5p) are altered in AD patients. All 6 miRNAs are strongly enriched in neurons. Upregulating these miRNAs in wild-type mice is however not causing AD-related cognitive disturbances.

CONCLUSION

Diverging AD-related neuropathologies induce common disturbances in the expression of neuronal miRNAs. 4 of these miRNAs are also upregulated in AD patients. Therefore these 4 miRNAs (miR-142a-5p, miR-146a-5p, miR-155-5p and miR-455-5p) appear part of a core pathological process in AD patients and APPtg and TAUtg mice. They are however not causing cognitive disturbances in wild-type mice. As some of these miRNA target AD relevant proteins, they may be, in contrast, part of a protective response in AD.

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Authors+Show Affiliations

Sierksma A
VIB Center for Brain & Disease Research, Leuven, Belgium. Department of Neurosciences, Leuven research Institute for Neuroscience and Disease (LIND), KU Leuven, Leuven, Belgium.
Lu A
VIB Center for Brain & Disease Research, Leuven, Belgium. Department of Neurosciences, Leuven research Institute for Neuroscience and Disease (LIND), KU Leuven, Leuven, Belgium.
Salta E
VIB Center for Brain & Disease Research, Leuven, Belgium. Department of Neurosciences, Leuven research Institute for Neuroscience and Disease (LIND), KU Leuven, Leuven, Belgium.
Vanden Eynden E
VIB Center for Brain & Disease Research, Leuven, Belgium. Department of Neurosciences, Leuven research Institute for Neuroscience and Disease (LIND), KU Leuven, Leuven, Belgium.
Callaerts-Vegh Z
Faculty of Psychology and Educational Sciences, Laboratory of Biological Psychology, KU Leuven, Leuven, Belgium.
D'Hooge R
Faculty of Psychology and Educational Sciences, Laboratory of Biological Psychology, KU Leuven, Leuven, Belgium.
Blum D
Université Lille, INSERM, CHU Lille, UMR-S 1172, LabEx DISTALZ, Alzheimer & Tauopathies, Lille, France.
Buée L
Université Lille, INSERM, CHU Lille, UMR-S 1172, LabEx DISTALZ, Alzheimer & Tauopathies, Lille, France.
Fiers M
VIB Center for Brain & Disease Research, Leuven, Belgium. mark.fiers@kuleuven.vib.be. Department of Neurosciences, Leuven research Institute for Neuroscience and Disease (LIND), KU Leuven, Leuven, Belgium. mark.fiers@kuleuven.vib.be.
De Strooper B
VIB Center for Brain & Disease Research, Leuven, Belgium. bart.destrooper@kuleuven.vib.be. Department of Neurosciences, Leuven research Institute for Neuroscience and Disease (LIND), KU Leuven, Leuven, Belgium. bart.destrooper@kuleuven.vib.be. Dementia Research Institute UK, ION, University College London, London, UK. bart.destrooper@kuleuven.vib.be.

MeSH

Alzheimer DiseaseAmyloid beta-PeptidesAnimalsDisease Models, AnimalHippocampusMice, TransgenicMicroRNAsNeuronsReal-Time Polymerase Chain ReactionUp-Regulationtau Proteins

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

30314521

Citation

Sierksma, Annerieke, et al. "Deregulation of Neuronal miRNAs Induced By Amyloid-β or TAU Pathology." Molecular Neurodegeneration, vol. 13, no. 1, 2018, p. 54.
Sierksma A, Lu A, Salta E, et al. Deregulation of neuronal miRNAs induced by amyloid-β or TAU pathology. Mol Neurodegener. 2018;13(1):54.
Sierksma, A., Lu, A., Salta, E., Vanden Eynden, E., Callaerts-Vegh, Z., D'Hooge, R., Blum, D., Buée, L., Fiers, M., & De Strooper, B. (2018). Deregulation of neuronal miRNAs induced by amyloid-β or TAU pathology. Molecular Neurodegeneration, 13(1), 54. https://doi.org/10.1186/s13024-018-0285-1
Sierksma A, et al. Deregulation of Neuronal miRNAs Induced By Amyloid-β or TAU Pathology. Mol Neurodegener. 2018 10 12;13(1):54. PubMed PMID: 30314521.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Deregulation of neuronal miRNAs induced by amyloid-β or TAU pathology. AU - Sierksma,Annerieke, AU - Lu,Ashley, AU - Salta,Evgenia, AU - Vanden Eynden,Elke, AU - Callaerts-Vegh,Zsuzsanna, AU - D'Hooge,Rudi, AU - Blum,David, AU - Buée,Luc, AU - Fiers,Mark, AU - De Strooper,Bart, Y1 - 2018/10/12/ PY - 2018/04/13/received PY - 2018/09/27/accepted PY - 2018/10/14/entrez PY - 2018/10/14/pubmed PY - 2019/1/31/medline KW - Alzheimer’s disease KW - In situ hybridization KW - miR-mimic KW - miRNA-seq KW - microRNA SP - 54 EP - 54 JF - Molecular neurodegeneration JO - Mol Neurodegener VL - 13 IS - 1 N2 - BACKGROUND: Despite diverging levels of amyloid-β (Aβ) and TAU pathology, different mouse models, as well as sporadic AD patients show predictable patterns of episodic memory loss. MicroRNA (miRNA) deregulation is well established in AD brain but it is unclear whether Aβ or TAU pathology drives those alterations and whether miRNA changes contribute to cognitive decline. METHODS: miRNAseq was performed on cognitively intact (4 months) and impaired (10 months) male APPtg (APPswe/PS1L166P) and TAUtg (THY-Tau22) mice and their wild-type littermates (APPwt and TAUwt). We analyzed the hippocampi of 12 mice per experimental group (n = 96 in total), and employed a 2-way linear model to extract differentially expressed miRNAs. Results were confirmed by qPCR in a separate cohort of 4 M and 10 M APPtg and APPwt mice (n = 7-9 per group) and in human sporadic AD and non-demented control brain. Fluorescent in situ hybridization identified their cellular expression. Functional annotation of predicted targets was performed using GO enrichment. Behavior of wild-type mice was assessed after intracerebroventricular infusion of miRNA mimics. RESULTS: Six miRNAs (miR-10a-5p, miR-142a-5p, miR-146a-5p, miR-155-5p, miR-211-5p, miR-455-5p) are commonly upregulated between APPtg and TAUtg mice, and four of these (miR-142a-5p, miR-146a-5p, miR-155-5p and miR-455-5p) are altered in AD patients. All 6 miRNAs are strongly enriched in neurons. Upregulating these miRNAs in wild-type mice is however not causing AD-related cognitive disturbances. CONCLUSION: Diverging AD-related neuropathologies induce common disturbances in the expression of neuronal miRNAs. 4 of these miRNAs are also upregulated in AD patients. Therefore these 4 miRNAs (miR-142a-5p, miR-146a-5p, miR-155-5p and miR-455-5p) appear part of a core pathological process in AD patients and APPtg and TAUtg mice. They are however not causing cognitive disturbances in wild-type mice. As some of these miRNA target AD relevant proteins, they may be, in contrast, part of a protective response in AD. SN - 1750-1326 UR - https://www.unboundmedicine.com/medline/citation/30314521/Deregulation_of_neuronal_miRNAs_induced_by_amyloid_β_or_TAU_pathology_ DB - PRIME DP - Unbound Medicine ER -