Debomoy K. Lahiri1, Justin M. Long1, Nipun Chopra1, Xudong Huang2, Nigel H. Greig3, Kumar Sambamurti4, Jack T. Rogers2, Weihong Song5 and Bryan Maloney1
1Department of Psychiatry, Neuroscience Research Center, Indiana University School of Medicine, Indianapolis, IN
46202,
2Departments of Psychiatry and Neurology, Massachusetts General Hospital and Harvard Medical School,
Charlestown, MA 02129, USA
3National Institute on Aging, NIH, Baltimore, MD 21224, USA
4Medical University South Carolina, Charleston, SC 29425, USA
5Department of Psychiatry, University of British Columbia, Vancouver, BC, Canada
Alzheimer’s disease (AD) is the most common form of dementia. Advances in “Research on Alzheimer’s disease” (ROAD), as reported in Current Alzheimer Research’ (CAR) and other journals, unveil many opportunities to tackle the disease but also unmask many potholes in our understanding of the disease process. Safe driving requires sensitive and responsive “brakes”. What are such brakes on the path down neurodegeneration? We argue for microRNA (miRNA). Several specific miRNAs regulate expression of AD pathway proteins, such as amyloid-β (Aβ) peptide precursor protein (APP), β-site APP-cleaving enzyme (BACE1) and neprilysin (MME). AD is characterized by excessive Aβ-loaded neuritic plaques and may result from misregulation of production or clearance of Aβ. The rate-limiting step in production of Aβ is processing of APP by the β-secretase, BACE1. MME is a major Aβ-clearing enzyme. We demonstrate miRNA-mediated regulation of APP and BACE1. We have recently reported specific microRNA species that regulate APP or BACE1 expression (Long et al., J. Biol. Chem., 2012; 2014). For the present work, we prepared either APP-, BACE1- or MME 3’-UTR plus the reporter vector by inserting the respective 3’-UTRs downstream from a Renilla luciferase gene and delivered the construct into human primary cultures, along with miRNAs predicted to target the respective 3'-UTRs. miR-153 reduced APP, and miR-298 and miR-339-5p reduced BACE1 reporter expression. Western analysis revealed reduction of native APP or BACE1 levels following specific miRNA-delivery. Specific interaction was confirmed by delivery of respective antagomirs and target protectors in primary human brain cultures. Notably, miR-339-5p levels were reduced in brains from AD patients vs age-matched controls. Our results reveal novel regulatory interaction between two important AD-related genes (APP and BACE1) and specific endogenously expressed miRNA species. These interactions may serve as novel and superior therapeutic targets against AD to conventional drug strategies. miRNA “slows” protein expression like a chicane in Grand Prix and does not completely block it, which may reduce interference in other physiological functions.
This work is supported by grants from Alzheimer’s Association and NIH.