The rat brain transcriptome: from infancy to aging and sporadic Alzheimer’s disease-like pathology

Abstract

Functional traits of the adult brain, which are established early in life, may impact susceptibility to Alzheimer’s disease (AD). Results from prior research conducted on senescence-accelerated OXYS rats, a prominent model for sporadic AD, provide evidence in favor of this hypothesis. The present study examined the transcriptomes of the prefrontal cortex (PFC) and hippocampus in OXYS and Wistar rats (control) during the early postnatal period (at age P3 and P10; P: postnatal day of life) to identify the signaling pathways and processes that contribute to delayed brain maturation in OXYS rats and assess their potential role in the development of AD traits later in life. Next, we compared the differentially expressed genes (DEGs) in the rat PFC and hippocampus throughout the five stages of AD-like pathology, from infancy to the progressive stage. Additionally, we noted conspicuous variations between the strains in the number of DEGs throughout all five ages. Significant differences were found in the number of DEGs between OXYS rats and Wistar rats in both brain structures at both P3 and P10. Notably, changes in gene expression patterns in the PFC and hippocampus of OXYS rats at 3 and 10 days of age are broadly associated with all basic mechanisms involved in Alzheimer’s pathogenesis, which are modified in OXYS rats at different stages of AD. Gene expression changes at P3 and P10 are associated with molecular processes including neuronal plasticity, immune responses, cerebrovascular function, and mitochondrial function. Remarkably, changes in the expression of genes associated with Aβ function were detected. The expression profile of genes linked to APP processing in the brain of OXYS rats is reduced during the early postnatal period. An intriguing finding, with potential significance for the development of AD pathology, is the decreased expression of the Abca7 gene, an important genetic factor of late-onset AD, in both brain regions of OXYS rats during the early postnatal period. The data demonstrated a decrease in Abca7 expression in the brains of OXYS rats at P20 and at 5 and 18 months (p 0.05). Additionally, three genes (Thoc3, Exosc8, and Smpd4) demonstrated overexpression in both brain regions of OXYS rats throughout their lifetimes. In conclusion, we have conducted a comparative analysis of changes in the rat brain transcriptomes from infancy to the advanced stage of AD-like pathology for the first time. The significant and comparable distinctions in gene expression and related processes were noteworthy during the early postnatal timeframe and in the severe stage of the pathology. Our findings indicate that a reduction in the effectiveness of neural network formation in the brain of OXYS rats at an early age is a clear contributor to AD symptomatology. The cause of this phenomenon remains unclear. However, we can identify shortened gestational age, low birth weight, and delayed brain development in infancy as major risk factors for the emergence of a disease-like pathology later in life, as these conditions are typically found in affected rats. Further investigation is needed to determine the causal relation between delayed brain development in infancy and neurodegeneration.