Age‑related brainstem degeneration through microRNA modulation in mice

Kawakita,Rie; Takata,Tadayuki; Nonaka,Wakako; Hamada,Yasuhiro; Iwama,Hisakazu; Kobara,Hideki; Deguchi,Kazushi; Miyamoto,Osamu; Nakamura,Takehiro; Itano,Toshifumi; Masaki,Tsutomu

doi:10.3892/mmr.2023.13032

Age‑related brainstem degeneration through microRNA modulation in mice

Authors:
- Rie Kawakita
- Tadayuki Takata
- Wakako Nonaka
- Yasuhiro Hamada
- Hisakazu Iwama
- Hideki Kobara
- Kazushi Deguchi
- Osamu Miyamoto
- Takehiro Nakamura
- Toshifumi Itano
- Tsutomu Masaki
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Affiliations: Department of Neurology, Faculty of Medicine, Kagawa University, Miki, Kagawa 761-0793, Japan, Life Science Research Center, Faculty of Medicine, Kagawa University, Miki, Kagawa 761-0793, Japan, Department of Gastroenterology, Faculty of Medicine, Kagawa University, Miki, Kagawa 761-0793, Japan, Department of Medical Engineering, Faculty of Health Science and Technology, Kawasaki University of Medical Welfare, Kurashiki, Okayama 701-0193, Japan, Department of Physiology 2, Kawasaki Medical School, Kurashiki, Okayama 701-0192, Japan
Published online on: June 13, 2023 https://doi.org/10.3892/mmr.2023.13032
Article Number: 146
Copyright: © Kawakita et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

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Abstract

Histopathological changes occur in the brainstem during the early stages of Alzheimer's disease (AD), with the pathological changes of the brain lesions ascending progressively in accordance with the Braak staging system. The senescence‑accelerated mouse prone 8 (SAMP8) mouse model has been previously used as a model of age‑dependent neurodegenerative diseases, including AD. In the present study, microRNAs (miRNAs) that were upregulated or downregulated in SAMP8 brainstems were identified using miRNA profiling of samples obtained from miRNA arrays. The preliminary stage of cognitive dysfunction was examined using male 5‑month‑old SAMP8 mice, with age‑matched senescence‑accelerated mouse resistant 1 mice as controls. A Y‑maze alternation test was performed to assess short‑term working memory and miRNA profiling was performed in each region of the dissected brain (brainstem, hippocampus and cerebral cortex). SAMP8 mice tended to be hyperactive, but short‑term working memory was preserved. Two miRNAs were upregulated (miR‑491‑5p and miR‑764‑5p) and two were downregulated (miR‑30e‑3p and miR‑323‑3p) in SAMP8 brainstems. In SAMP8 mice, the expression level of upregulated miRNAs were the highest in the brainstem, wherein age‑related brain degeneration occurs early. It was demonstrated that the order of specific miRNA expression levels corresponded to the progression order of age‑related brain degeneration. Differentially expressed miRNAs regulate multiple processes, including neuronal cell death and neuron formation. Changes in miRNA expression may result in the induction of target proteins during the early stages of neurodegeneration in the brainstem. These findings suggest that studying altered miRNA expression may provide molecular evidence for early age‑related neuropathological changes.

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