Abstract
The testing of pathological biomarkers of Alzheimer’s disease (AD), such as amyloid beta and tau, is time-consuming, expensive, and invasive. Here, we used 3xTg-AD mice to identify and validate putative novel blood transcriptome biomarkers of AD that can potentially be identified in the blood of patients. mRNA was extracted from the blood and hippocampus of 3xTg-AD and control mice at different ages and used for microarray analysis. Network and functional analyses revealed that the differentially expressed genes between AD and control mice modulated the immune and neuroinflammation systems. Five novel gene transcripts (Cdkn2a, Apobec3, Magi2, Parp3, and Cass4) showed significant increases with age, and their expression in the blood was collated with that in the hippocampus only in AD mice. We further assessed previously identified candidate biomarker genes. The expression of Trem1 and Trem2 in both the blood and brain was significantly increased with age. Decreased Tomm40 and increased Pink1 mRNA levels were observed in the mouse blood. The changes in the expression of Snca and Apoe mRNA in the mouse blood and brain were similar to those found in human AD blood. Our results demonstrated that the immune and neuroinflammatory system is involved in the pathophysiologies of aging and AD and that the blood transcriptome might be useful as a biomarker of AD.
Highlights
The diagnosis of Alzheimer’s disease (AD) is mainly based on the assessment of clinical symptoms and cognitive tests
The analysis of gene expression revealed positive correlations among the same tissues from the mice belonging to the same group, such as between the AD12 and AD52 hip samples, whereas negative correlations were found among the same tissues from mice belonging to different groups, such as between the AD and C hip samples
Consistent with our previous studies, which showed higher TREM1 and TREM2 mRNA levels in the human AD blood [8,9,10], the levels of these mRNAs in the control mouse blood tended to increase with age. These results suggest that higher TREM1 and TREM2 mRNA levels in human AD blood might reflect abnormal aging rather than pathophysiological changes in AD
Summary
The diagnosis of Alzheimer’s disease (AD) is mainly based on the assessment of clinical symptoms and cognitive tests. Several tools are used for the diagnosis of AD, and these include the identification of biomarkers from brain scans and lumbar puncture procedures. The levels of amyloid beta and tau proteins in the cerebrospinal fluid and those detected by positron emission tomography are highly accurate markers for the detection of AD pathology in the brain. The assessment of these biomarkers is invasive and time- and cost-consuming [1]. Shinichiro Ochi and Jun-ichi Iga contributed to this work.
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