Abstract
The locus coeruleus (LC), which contains the largest group of noradrenergic neurons in the central nervous system innervating the telencephalon, is an early and constantly vulnerable region to neurofibrillary tangle (NFT) pathology in aging and Alzheimer's disease (AD). The present study using whole genome bisulfite sequencing and Infinium Human Methylation 450 BeadChip was designed to learn about DNA methylation profiles in LC with age and NFT pathology. This method identified decreased DNA methylation of Katanin-Interacting Protein gene (KIAA0566) linked to age and presence of NFT pathology. KIAA0566 mRNA expression demonstrated with RT-qPCR significantly decreased in cases with NFT pathology. Importantly, KIAA0566 immunoreactivity was significantly decreased only in LC neurons with NFTs, but not in neurons without tau pathology when compared with neurons of middle-aged individuals. These changes were accompanied by a similar pattern of selective p80-katanin reduced protein expression in neurons with NFTs. In contrast, p60-katanin subunit expression levels in the neuropil were similar in MA cases and cases with NFT pathology. Since katanin is a major microtubule-severing protein and KIAA0566 binds and interacts with katanin, de-regulation of the katanin-signaling pathway may have implications in the regulation of microtubule homeostasis in LC neurons with NFTs, thereby potentially interfering with maintenance of the cytoskeleton and transport.
Highlights
Studies of Alzheimer’s disease (AD) are mainly focused on the entorhinal cortex, hippocampus, and neocortex because of the massive accumulation with disease progression of β-amyloid deposits and hyper-phosphorylated tau-containing neurofibrillary tangles (NFTs), neuropil threads, and dystrophic neurites in these regions
DNA methylation profiles obtained from this platform showed a few differential methylation regions (DMRs) when comparing MA individuals with cases showing various stages of NFT pathology
Two significant DMRs, UTRN and KIAA0556 genes, coding for utrophin and kataninInteracting Protein, respectively, were differentially hypomethylated in cases with NFT pathology when compared with MA individuals
Summary
Studies of Alzheimer’s disease (AD) are mainly focused on the entorhinal cortex, hippocampus, and neocortex because of the massive accumulation with disease progression of β-amyloid deposits (diffuse and senile plaques) and hyper-phosphorylated tau-containing neurofibrillary tangles (NFTs), neuropil threads, and dystrophic neurites in these regions. MicroRNA expression is altered in the LC at early stages of NFT pathology (Llorens et al, 2017). These observations indicate alterations in the mechanisms leading to gene transcription and protein translation in LC at early stages of AD-related pathology. Since one of the differentially methylated genes is KIAA0556, which encodes katanin-Interacting Protein, the study is redirected to the analysis of expression of KIAA0556 mRNA and protein, and the proteins katanin subunit 60 and katanin subunit 80 (p60-katanin and p80-katanin, respectively) to assess possible alterations in katanin pathway signaling linked to NFT pathology in LC
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