D.K. Lahiri, N. Chopra, K. Nudelman, K. Nho, J.T. Rogers, N.H. Greig, K. Sambamurti and A.J. Saykin
Department of Psychiatry and of Medical & Molecular Genetics, IADC, Indiana University School of Medicine, Indianapolis, IN, USA
The ENCODE project reveals that over 80% of the human genome is biologically active; however, only a small portion encodes for protein. The vast amount of RNA transcribed but not translated into protein can be grouped into housekeeping RNA and regulatory RNA. Small non-coding RNAs, in particular, have been the focus of many studies and their fundamental roles in neurodegenerative diseases are currently being investigated. MicroRNAs (miRNAs) are non-coding small RNAs that are master regulators of genic expression and consequently of many cellular processes. But their expression is often deregulated in human diseases, including Alzheimer's disease (AD). Recently miRNAs were discovered in body fluids (serum, plasma) and brain tissues and their levels have often been reported to be altered in patients. Here we present evidence to show how particular miRNA species regulate neuronal genes involved in AD using neuronal cultures and human brain tissue specimens from control and AD subjects. AD associated with over-production of amyloid-β peptide (Aβ), a proteolytic product of Aβ precursor protein (APP). Expression studies suggest that dysregulation of proteins involved in Aβ production, such as APP and β-secretase (BACE1), and/or Aβ degradation, such as neprilysin (NEP), contribute to excess Aβ deposition. Elucidating the regulation of these proteins’ expression may ultimately reveal new drug targets. We report the regulation of these gene products by specific miRNAs. Our results reveal a novel regulatory interaction between important AD-related genes (APP, BACE1 and NEP) and specific endogenously-expressed miRNA species. We also observed specific miRNAs regulating APP levels via interactions with the APP-3’UTR or APP-5’UTR in human primary neuronal cultures. Recent neuroimaging and genetic studies further shed light on the role of miRNAs in AD. These regulatory interactions may serve as novel therapeutic targets and enable the development of treatment strategies beneficial for AD.
“We thank the sponsors of this research including the National Institute on Aging (US NIH), Indiana Clinical & Translational Sciences Institute (ICTSI) and Indiana State Dept. of Health Spinal Cord and Brain Injury Research Fund”.