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Splicing transcriptome analysis reveals retained introns in retinal genes of the 5xFAD mouse, suggesting early diagnosis of Alzheimer’s disease through vision impairment

ABSTRACT: Alzheimer’s disease (AD) is an age-related neurodegenerative disorder in which neuronal and synaptic loss of the brain leads to cognitive impairment and dementia. Therefore, the early diagnosis of AD with various biomarkers is important for the prevention and treatment. Although retina pathology is emerging biomarker that associated with AD, detailed molecular mechanisms of retinal impairments remain unclear. Here, we identify the genome-wide dysfunction of alternative splicing in the early stage of 5xFAD transgenic mouse retina by the RNA-seq analysis. Especially, retained intron (RI) highly enriched in phototransduction and retinal genes of 1.5-month-old 5xFAD mouse retina that significantly associated with retinal physiological impairment of rod photoreceptors by electroretinogram (ERG) analysis. These results indicate that the abnormal scotopic ERG associated with global splicing impairment may be useful early detection biomarker for AD.

ORGANISM(S): Mus musculus

PROVIDER: GSE274214 | GEO | 2025/07/06

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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Splicing transcriptome analysis reveals retained introns in retinal genes of the 5xFAD mouse, suggesting early diagnosis of Alzheimer’s disease through vision impairment

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