Age-related brainstem degeneration through microRNA modulation in mice

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 hyperac- tive, 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 neuro- degeneration in the brainstem. These findings suggest that studying altered miRNA expression may provide molecular evidence for early age-related neuropathological changes.