Altered microRNA, mRNA, and Protein Expression of Neurodegeneration-Related Biomarkers and Their Transcriptional and Epigenetic Modifiers in a Human Tau Transgenic Mouse Model in Response to Developmental Lead Exposure
Affiliations: [a] Department of Biomedical and Pharmaceutical Science, University of Rhode Island, Kingston RI, USA
| [b] Interdisciplinary Neuroscience Program, University of Rhode Island, Kingston RI, USA
| [c] George and Anne Ryan Institute for Neuroscience, University of Rhode Island, Kingston RI, USA
| [d] Biochemical Technology Program, Faculty of Applied Science, Thamar University, Thamar, Yemen
| [e] Department of Pharmacology and Toxicology, College of Pharmacy, University of Hail, Hail, Kingdom of Saudi Arabia
Correspondence:
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Correspondence to: Nasser H. Zawia, PhD, Department of Biomedical and Pharmaceutical Sciences, University of Rhode Island, Kingston, RI, 02881, USA. Tel.: +1 401 874 2663; Fax: +1 401 874 5491; E-mail: [email protected].
Abstract: Amyloid deposits originating from the amyloid-β protein precursor (AβPP) and aggregates of the microtubule associated protein tau (MAPT) are the hallmarks of Alzheimer’s disease (AD). Animal studies have demonstrated a link between early life exposure to lead (Pb) and latent overexpression of the AβPP and MAPT genes and their products via epigenetic reprogramming. The present study monitored APP gene and epigenetic mediators and transcription factors known to regulate it. Western blot analysis and quantitative polymerase chain reaction (qPCR) were used to study the mRNA, miRNA, and protein levels of AβPP, specificity protein 1 (SP1; a transcriptional regulator of amyloid and tau pathway), and epigenetic intermediates namely: DNA methyltransferase (DNMT) 1, DNMT3a and Methyl– CpG protein binding 2 (MeCP2) in the cerebral cortex of transgenic mice (Knock-in for human MAPT). These transgenic mice were developmentally exposed to Pb and the impact on mRNA, miRNA, and protein levels was scrutinized on postnatal days (PND) 20 and 50. The data revealed a consistent inverse relationship between miRNA and protein levels for SP1 and AβPP both in the basal and exposed conditions, which may influence the levels of their corresponding proteins. On the other hand, the relationship between miRNA and protein levels was not correlative for DNMT1 and DNMT3a. MeCP2 miRNA protein levels corresponded only following environmental exposure. These results suggest that developmental exposure to Pb and subsequent AβPP protein levels may be controlled through transcriptional regulators and epigenetic mechanisms that mainly involve miRNA regulation.
