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Next-generation sequencing of wild type and 5XFAD transcriptomes for Alzheimer's disease study

ABSTRACT: We found some novel miRNA that targets SIRT1 may contribute to the pathogenesis in AD mouse model. We first identified that SIRT1 is significantly reduced in Alzheimer patient`s precentral gyrus and 5XFAD mice. To determine whether the strategy of inhibiting some miRNA affects AD pathology, we synthesized antisense oligonucleotides of miRNA (miRNA ASO) and studied this sequence in the brain of 5XFAD through direct intracerebral ventricular injection using stereotaxic instrument. We identified miRNA ASO significantly reduced amyloid beta plaque and amyloid production enzyme. Importantly, the attenuation of amyloid beta plaques through miRNA ASO was caused by a phagocytic activity of glial cells, by which it can directly target CD36. miRNA ASO also decreases inflammatory responses. These results inhibit neuronal loss caused by amyloid beta and leading to improvement of cognitive impairment. These insights of miRNA ASO suggests as therapeutic scope against AD pathology.

ORGANISM(S): Mus musculus

PROVIDER: GSE142633 | GEO | 2019/12/27

REPOSITORIES: GEO

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Project description:Alzheimer’s disease (AD) is an unremitting neurodegenerative disorder characterized by cerebral amyloid-β (Aβ) accumulation and gradual decline in cognitive function. Changes in brain energy metabolism arise in the preclinical phase of AD, suggesting an important metabolic component of early AD pathology. Neurons and astrocytes function in close metabolic collaboration, which is essential for the recycling of neurotransmitters in the synapse. However, how this metabolic interplay may be affected during the early stages of AD development has not been sufficiently investigated. Here, we provide an integrative analysis of cellular metabolism during the early stages of Aβ accumulation in the cerebral cortex and hippocampus of the 5xFAD mouse model of AD. Our electrophysiological examination revealed an increase in spontaneous excitatory signaling in hippocampal brain slices of 5xFAD mice. This hyperactive neuronal phenotype coincided with decreased hippocampal TCA cycle metabolism mapped by stable 13C isotope tracing. Particularly, reduced astrocyte TCA cycle activity led to decreased glutamine synthesis, in turn hampering neuronal GABA synthesis in the 5xFAD hippocampus. In contrast, cerebral cortical slices of 5xFAD mice displayed an elevated capacity for oxidative glucose metabolism suggesting a metabolic compensation. When we explored the brain proteome and metabolome of the 5xFAD mice, we found limited changes, supporting that the functional metabolic disturbances between neurons and astrocytes are early events in AD pathology. In addition, we show that synaptic mitochondrial and glycolytic function was impaired selectively in the 5xFAD hippocampus, whereas non-synaptic mitochondrial function was maintained. These findings were supported by ultrastructural analyses demonstrating disruptions in mitochondrial morphology, particularly in the 5xFAD hippocampus. Collectively, our study reveals complex region and cell specific metabolic adaptations, in the early stages of amyloid pathology, which may be fundamental for the progressing synaptic dysfunction in AD.

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Next-generation sequencing of wild type and 5XFAD transcriptomes for Alzheimer's disease study

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