title: Abnormal gephyrin immunoreactivity associated with Alzheimer disease pathologic changes.
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.
authors.affiliation: From the Department of Neurology (CMH, HR, AIL, JJL, TSW), Center for Neurodegenerative Disease (CMH, HR, NTS, EBD, DMD, MG, AIL, JJL, TSW), Departments of Biochemistry (NTS) and Human Genetics (EBD, TSW), and Pathology and Laboratory Medicine (MG), Emory University School of Medicine, Atlanta, Georgia; Department of Pathology, University of Washington, Seattle, Washington (TJM); Departments of Pathology and Neurology, Johns Hopkins School of Medicine, Baltimore, Maryland (JCT); National Institute of Aging, National Institutes of Health, Bethesda, Maryland (MT); and Atlanta Veterans Administration Medical Center, Atlanta, Georgia (TSW).
authors.forename: Chadwick M
authors.initials: CM
authors.lastname: Hales
authors.forename: Howard
authors.initials: H
authors.lastname: Rees
authors.forename: Nicholas T
authors.initials: NT
authors.lastname: Seyfried
authors.forename: Eric B
authors.initials: EB
authors.lastname: Dammer
authors.forename: Duc M
authors.initials: DM
authors.lastname: Duong
authors.forename: Marla
authors.initials: M
authors.lastname: Gearing
authors.forename: Thomas J
authors.initials: TJ
authors.lastname: Montine
authors.forename: Juan C
authors.initials: JC
authors.lastname: Troncoso
authors.forename: Madhav
authors.initials: M
authors.lastname: Thambisetty
authors.forename: Allan I
authors.initials: AI
authors.lastname: Levey
authors.forename: James J
authors.initials: JJ
authors.lastname: Lah
authors.forename: Thomas S
authors.initials: TS
authors.lastname: Wingo
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000544:Alzheimer Disease / Q000378:metabolism* / Q000473:pathology; D001921:Brain / Q000378:metabolism* / Q000473:pathology; D002352:Carrier Proteins / Q000378:metabolism*; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D008297:Male; D008565:Membrane Proteins / Q000378:metabolism*; D008875:Middle Aged; D016874:Neurofibrillary Tangles / Q000378:metabolism* / Q000473:pathology; D058225:Plaque, Amyloid / Q000378:metabolism* / Q000473:pathology
chemical_list: D002352:Carrier Proteins; D008565:Membrane Proteins; C073441:gephyrin