Cargando…
MUTYH Actively Contributes to Microglial Activation and Impaired Neurogenesis in the Pathogenesis of Alzheimer's Disease
Oxidative stress is a major risk factor for Alzheimer's disease (AD), which is characterized by brain atrophy, amyloid plaques, neurofibrillary tangles, and loss of neurons. 8-Oxoguanine, a major oxidatively generated nucleobase highly accumulated in the AD brain, is known to cause neurodegener...
Autores principales: | , , , , , , , , , , |
---|---|
Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Hindawi
2021
|
Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8714343/ https://www.ncbi.nlm.nih.gov/pubmed/34970419 http://dx.doi.org/10.1155/2021/8635088 |
_version_ | 1784623895379181568 |
---|---|
author | Mizuno, Yuri Abolhassani, Nona Mazzei, Guianfranco Sakumi, Kunihiko Saito, Takashi Saido, Takaomi C. Ninomiya, Toshiharu Iwaki, Toru Yamasaki, Ryo Kira, Jun-ichi Nakabeppu, Yusaku |
author_facet | Mizuno, Yuri Abolhassani, Nona Mazzei, Guianfranco Sakumi, Kunihiko Saito, Takashi Saido, Takaomi C. Ninomiya, Toshiharu Iwaki, Toru Yamasaki, Ryo Kira, Jun-ichi Nakabeppu, Yusaku |
author_sort | Mizuno, Yuri |
collection | PubMed |
description | Oxidative stress is a major risk factor for Alzheimer's disease (AD), which is characterized by brain atrophy, amyloid plaques, neurofibrillary tangles, and loss of neurons. 8-Oxoguanine, a major oxidatively generated nucleobase highly accumulated in the AD brain, is known to cause neurodegeneration. In mammalian cells, several enzymes play essential roles in minimizing the 8-oxoguanine accumulation in DNA. MUTYH with adenine DNA glycosylase activity excises adenine inserted opposite 8-oxoguanine in DNA. MUTYH is reported to actively contribute to the neurodegenerative process in Parkinson and Huntington diseases and some mouse models of neurodegenerative diseases by accelerating neuronal dysfunction and microgliosis under oxidative conditions; however, whether or not MUTYH is involved in AD pathogenesis remains unclear. In the present study, we examined the contribution of MUTYH to the AD pathogenesis. Using postmortem human brains, we showed that various types of MUTYH transcripts and proteins are expressed in most hippocampal neurons and glia in both non-AD and AD brains. We further introduced MUTYH deficiency into App(NL-G-F/NL-G-F) knock-in AD model mice, which produce humanized toxic amyloid-β without the overexpression of APP protein, and investigated the effects of MUTYH deficiency on the behavior, pathology, gene expression, and neurogenesis. MUTYH deficiency improved memory impairment in App(NL-G-F/NL-G-F) mice, accompanied by reduced microgliosis. Gene expression profiling strongly suggested that MUTYH is involved in the microglial response pathways under AD pathology and contributes to the phagocytic activity of disease-associated microglia. We also found that MUTYH deficiency ameliorates impaired neurogenesis in the hippocampus, thus improving memory impairment. In conclusion, we propose that MUTYH, which is expressed in the hippocampus of AD patients as well as non-AD subjects, actively contributes to memory impairment by inducing microgliosis with poor neurogenesis in the preclinical AD phase and that MUTYH is a novel therapeutic target for AD, as its deficiency is highly beneficial for ameliorating AD pathogenesis. |
format | Online Article Text |
id | pubmed-8714343 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2021 |
publisher | Hindawi |
record_format | MEDLINE/PubMed |
spelling | pubmed-87143432021-12-29 MUTYH Actively Contributes to Microglial Activation and Impaired Neurogenesis in the Pathogenesis of Alzheimer's Disease Mizuno, Yuri Abolhassani, Nona Mazzei, Guianfranco Sakumi, Kunihiko Saito, Takashi Saido, Takaomi C. Ninomiya, Toshiharu Iwaki, Toru Yamasaki, Ryo Kira, Jun-ichi Nakabeppu, Yusaku Oxid Med Cell Longev Research Article Oxidative stress is a major risk factor for Alzheimer's disease (AD), which is characterized by brain atrophy, amyloid plaques, neurofibrillary tangles, and loss of neurons. 8-Oxoguanine, a major oxidatively generated nucleobase highly accumulated in the AD brain, is known to cause neurodegeneration. In mammalian cells, several enzymes play essential roles in minimizing the 8-oxoguanine accumulation in DNA. MUTYH with adenine DNA glycosylase activity excises adenine inserted opposite 8-oxoguanine in DNA. MUTYH is reported to actively contribute to the neurodegenerative process in Parkinson and Huntington diseases and some mouse models of neurodegenerative diseases by accelerating neuronal dysfunction and microgliosis under oxidative conditions; however, whether or not MUTYH is involved in AD pathogenesis remains unclear. In the present study, we examined the contribution of MUTYH to the AD pathogenesis. Using postmortem human brains, we showed that various types of MUTYH transcripts and proteins are expressed in most hippocampal neurons and glia in both non-AD and AD brains. We further introduced MUTYH deficiency into App(NL-G-F/NL-G-F) knock-in AD model mice, which produce humanized toxic amyloid-β without the overexpression of APP protein, and investigated the effects of MUTYH deficiency on the behavior, pathology, gene expression, and neurogenesis. MUTYH deficiency improved memory impairment in App(NL-G-F/NL-G-F) mice, accompanied by reduced microgliosis. Gene expression profiling strongly suggested that MUTYH is involved in the microglial response pathways under AD pathology and contributes to the phagocytic activity of disease-associated microglia. We also found that MUTYH deficiency ameliorates impaired neurogenesis in the hippocampus, thus improving memory impairment. In conclusion, we propose that MUTYH, which is expressed in the hippocampus of AD patients as well as non-AD subjects, actively contributes to memory impairment by inducing microgliosis with poor neurogenesis in the preclinical AD phase and that MUTYH is a novel therapeutic target for AD, as its deficiency is highly beneficial for ameliorating AD pathogenesis. Hindawi 2021-12-21 /pmc/articles/PMC8714343/ /pubmed/34970419 http://dx.doi.org/10.1155/2021/8635088 Text en Copyright © 2021 Yuri Mizuno et al. https://creativecommons.org/licenses/by/4.0/This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. |
spellingShingle | Research Article Mizuno, Yuri Abolhassani, Nona Mazzei, Guianfranco Sakumi, Kunihiko Saito, Takashi Saido, Takaomi C. Ninomiya, Toshiharu Iwaki, Toru Yamasaki, Ryo Kira, Jun-ichi Nakabeppu, Yusaku MUTYH Actively Contributes to Microglial Activation and Impaired Neurogenesis in the Pathogenesis of Alzheimer's Disease |
title | MUTYH Actively Contributes to Microglial Activation and Impaired Neurogenesis in the Pathogenesis of Alzheimer's Disease |
title_full | MUTYH Actively Contributes to Microglial Activation and Impaired Neurogenesis in the Pathogenesis of Alzheimer's Disease |
title_fullStr | MUTYH Actively Contributes to Microglial Activation and Impaired Neurogenesis in the Pathogenesis of Alzheimer's Disease |
title_full_unstemmed | MUTYH Actively Contributes to Microglial Activation and Impaired Neurogenesis in the Pathogenesis of Alzheimer's Disease |
title_short | MUTYH Actively Contributes to Microglial Activation and Impaired Neurogenesis in the Pathogenesis of Alzheimer's Disease |
title_sort | mutyh actively contributes to microglial activation and impaired neurogenesis in the pathogenesis of alzheimer's disease |
topic | Research Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8714343/ https://www.ncbi.nlm.nih.gov/pubmed/34970419 http://dx.doi.org/10.1155/2021/8635088 |
work_keys_str_mv | AT mizunoyuri mutyhactivelycontributestomicroglialactivationandimpairedneurogenesisinthepathogenesisofalzheimersdisease AT abolhassaninona mutyhactivelycontributestomicroglialactivationandimpairedneurogenesisinthepathogenesisofalzheimersdisease AT mazzeiguianfranco mutyhactivelycontributestomicroglialactivationandimpairedneurogenesisinthepathogenesisofalzheimersdisease AT sakumikunihiko mutyhactivelycontributestomicroglialactivationandimpairedneurogenesisinthepathogenesisofalzheimersdisease AT saitotakashi mutyhactivelycontributestomicroglialactivationandimpairedneurogenesisinthepathogenesisofalzheimersdisease AT saidotakaomic mutyhactivelycontributestomicroglialactivationandimpairedneurogenesisinthepathogenesisofalzheimersdisease AT ninomiyatoshiharu mutyhactivelycontributestomicroglialactivationandimpairedneurogenesisinthepathogenesisofalzheimersdisease AT iwakitoru mutyhactivelycontributestomicroglialactivationandimpairedneurogenesisinthepathogenesisofalzheimersdisease AT yamasakiryo mutyhactivelycontributestomicroglialactivationandimpairedneurogenesisinthepathogenesisofalzheimersdisease AT kirajunichi mutyhactivelycontributestomicroglialactivationandimpairedneurogenesisinthepathogenesisofalzheimersdisease AT nakabeppuyusaku mutyhactivelycontributestomicroglialactivationandimpairedneurogenesisinthepathogenesisofalzheimersdisease |