Research ArticlesReduced miR-512 and the Elevated Expression of Its Targets cFLIP and MCL1 Localize to Neurons With Hyperphosphorylated Tau Protein in Alzheimer DiseaseMezache, Louisa BA*; Mikhail, Madison MA*; Garofalo, Michela PhD†; Nuovo, Gerard J. MD*,†Author Information *Phylogeny Inc. †OSU Comprehensive Cancer Center, Columbus, OH Supported by the Lewis Foundation. The authors declare no conflict of interest. Reprints: Gerard J. Nuovo, MD, 1476 Manning Parkway, Powell, OH 43065 (e-mail: [email protected]). Received June 24, 2014 Accepted September 1, 2014 Applied Immunohistochemistry & Molecular Morphology: October 2015 - Volume 23 - Issue 9 - p 615-623 doi: 10.1097/PAI.0000000000000147 Buy Metrics Abstract The cause for the neurofibrillary tangles and plaques in Alzheimer disease likely relates to an abnormal accumulation of their key components, which include β-amyloid and hyperphosphorylated tau protein. We segregated Alzheimer brain sections from people with end-stage disease into those with abundant hyperphosphorylated tau protein and those without and compared each to normal brains for global microRNA patterns. A significant reduced expression of several microRNAs, including miR-512, was evident in the Alzheimer brain sections with abundant hyperphosphorylated tau. Immunohistochemistry documented that 2 known targets of microRNA-512, cFLIP and MCL1, were significantly over expressed and each colocalized to neurons with the abnormal tau protein. Analysis for apoptosis including activated caspase-3, increased caspase-4 and caspase-8, apoptosis initiating factor, APAF-1 activity, and the TUNEL assay was negative in the areas where neurons showed hyperphosphorylated tau. MCM2 expression, a marker of neuroprogenitor cells, was significantly reduced in the Alzheimer sections that contained the hyperphosphorylated tau. These results suggest that a basic defect in Alzheimer disease may be the reduced microRNA-driven increased expression of proteins that may alter the apoptotic/antiapoptotic balance of neurons. This, in turn, could lead to the accumulation of key Alzheimer proteins such as hyperphosphorylated tau that ultimately prevent normal neuronal function and lead to disease symptomatology. Copyright 2015 Wolters Kluwer Health, Inc. All rights reserved.