Abnormal Gephyrin Immunoreactivity Associated With Alzheimer Disease Pathologic Changes

• Type of Material: Article
• Authors: Chadwick Hales, Emory University; Howard Rees, Emory University; Nicholas Seyfried, Emory University; Eric Dammer, Emory University; Duc M. Duong, Emory University; Marla Gearing, Emory University; Thomas J. Montine, University of Washington; Juan C. Troncoso, Johns Hopkins University; Madhav Thambisetty, National Institute on Aging; Allan I Levey, Emory University; James J Lah, Emory University; Thomas Wingo, Emory University
• Language: English
• Date: 2013-11-01
• Publisher: Oxford University Press (OUP): Policy B - Oxford Open Option B
• Publication Version: Author Accepted Manuscript (After Peer Review)
• Copyright Statement: Copyright © 2013 by the American Association of Neuropathologists, Inc.
• Final Published Version (URL): http://dx.doi.org/10.1097/01.jnen.0000435847.59828.db
• Title of Journal or Parent Work: Journal of Neuropathology and Experimental Neurology
• ISSN: 0022-3069
• Volume: 72
• Issue: 11
• Start Page: 1009
• End Page: 1015
• Grant/Funding Information: C.M.H.-American Brain Foundation Clinical Research Training Fellowship; A.I.L-Emory Alzheimer’s Disease Research Center-NIA-AG025688; J.J.L.-NIAP01AG014449; Emory Neuroscience NINDS Core Facility-P30NS055077; J. C. T-John’s Hopkins University Alzheimer’s Disease Research Center-NIA-AG005146 and Alzheimer’s Association-IIRG-09-134090;-T.S.W.-The Department of Veteran Affairs-CDA1-002-09F and 1IK2BX001820.
• Keywords: Science & Technology; Pathology; Life Sciences & Biomedicine; Gephyrin; beta-amyloid; VARIANTS; PREVALENCE; Neurosciences; GABA; Synapse; BETA; Alzheimer disease; Neurosciences & Neurology; GLYCINE RECEPTOR; Presenilin; Clinical Neurology
• Research Categories: Biology, Neuroscience; Chemistry, Biochemistry; Health Sciences, Pathology

Abstract

Many neurodegenerative disorders involve the abnormal accumulation of proteins. In addition to the pathologic hallmarks of neurofibrillary tangles and β-amyloid plaques in Alzheimer disease (AD), here we show that abnormal accumulations of gephyrin, an inhibitory receptor-anchoring protein, are highly correlated with the neuropathologic diagnosis of AD in 17 AD versus 14 control cases. Furthermore, gephyrin accumulations were specific for AD and not seen in normal controls or other neurodegenerative diseases including Parkinson disease, corticobasal degeneration, and frontotemporal degeneration. Gephyrin accumulations in AD overlapped with β-amyloid plaques and, more rarely, neurofibrillary tangles. Biochemical and proteomic studies of AD and control brain samples suggested alterations in gephyrin solubility and reveal elevated levels of gephyrin lower-molecular-weight species in the AD insoluble fraction. Because gephyrin is involved in synaptic organization and synaptic dysfunction is an early event in AD, these findings point to its possible role in the pathogenesis of AD.