Abstract
The senescence-accelerated mouse prone 8 (SAMP8) mouse model is a useful model for investigating the fundamental mechanisms involved in the age-related learning and memory deficits of Alzheimer’s disease (AD), while the SAM/resistant 1 (SAMR1) mouse model shows normal features. Recent evidence has shown that long non-coding RNAs (lncRNAs) may play an important role in AD pathogenesis. However, a comprehensive and systematic understanding of the function of AD-related lncRNAs and their associated nearby coding genes in AD is still lacking. In this study, we collected the hippocampus, the main area of AD pathological processes, of SAMP8 and SAMR1 animals and performed microarray analysis to identify aberrantly expressed lncRNAs and their associated nearby coding genes, which may contribute to AD pathogenesis. We identified 3,112 differentially expressed lncRNAs and 3,191 differentially expressed mRNAs in SAMP8 mice compared to SAMR1 mice. More than 70% of the deregulated lncRNAs were intergenic and exon sense-overlapping lncRNAs. Gene Ontology (GO) and pathway analyses of the AD-related transcripts were also performed and are described in detail, which imply that metabolic process reprograming was likely related to AD. Furthermore, six lncRNAs and six mRNAs were selected for further validation of the microarray results using quantitative PCR, and the results were consistent with the findings from the microarray. Moreover, we analyzed 780 lincRNAs (also called long “intergenic” non-coding RNAs) and their associated nearby coding genes. Among these lincRNAs, AK158400 had the most genes nearby (n = 13), all of which belonged to the histone cluster 1 family, suggesting regulation of the nucleosome structure of the chromosomal fiber by affecting nearby genes during AD progression. In addition, we also identified 97 aberrant antisense lncRNAs and their associated coding genes. It is likely that these dysregulated lncRNAs and their associated nearby coding genes play a role in the development and/or progression of AD.
Highlights
Alzheimer’s disease (AD) is considered an age-related neurodegenerative disease with a progressive impairment in cognitive function that is characterized by the presence of senile plaques and neurofibrillary tangles.[1,2] The hippocampus is one of the most important brain regions for learning and memory and is the main impaired region of AD.[3]
These results indicated that 8-month-old senescence-accelerated mouse prone 8 (SAMP8) mice exhibited severe learning and cognitive impairments and spontaneously developed AD, which was consistent with our previous studies.[19]
The results showed that a total of 21,314 aberrantly expressed long non-coding RNAs (lncRNAs) were identified in the hippocampal tissues of SAMP8 mice compared with age-matched senescence-accelerated mouse (SAM)/resistant 1 (SAMR1), of which 9,639 lncRNAs had upregulated expression and 11,675 displayed downregulated expression (Tables S1 and S2) in the SAMP8 mice
Summary
Alzheimer’s disease (AD) is considered an age-related neurodegenerative disease with a progressive impairment in cognitive function that is characterized by the presence of senile plaques and neurofibrillary tangles.[1,2] The hippocampus is one of the most important brain regions for learning and memory and is the main impaired region of AD.[3] The progressive memory deterioration of AD results in the loss of autonomy, and patients require full-time medical care.[4] there are no effective therapeutic strategies to prevent the progression of AD currently.[5] revealing the molecular mechanism of AD is necessary for developing effective therapy. The debate over whether senile plaques and neurofibrillary tangles are causative or merely markers of the disease has been ongoing for most of the past century. Despite considerable research, including studies of various genes and proteins in this area, the detailed mechanism of AD is still limited, and we should focus on molecules other than genes and proteins that may play an important role in AD
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