Abnormal Gephyrin immunoreactivity associated with Alzheimer disease pathologic changes

Chadwick M. Hales, Howard Rees, Nicholas T. Seyfried, Eric B. Dammer, Duc M. Duong, Marla Gearing, Thomas J. Montine, Juan C. Troncoso, Madhav Thambisetty, Allan I. Levey, James J. Lah, Thomas S. Wingo

Research output: Contribution to journalArticle

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.

Original languageEnglish (US)
Pages (from-to)1009-1015
Number of pages7
JournalJournal of neuropathology and experimental neurology
Volume72
Issue number11
DOIs
StatePublished - Nov 1 2013

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Keywords

  • Alzheimer disease
  • GABA
  • Gephyrin
  • Presenilin
  • Synapse
  • β-amyloid

ASJC Scopus subject areas

  • Pathology and Forensic Medicine
  • Neurology
  • Clinical Neurology
  • Cellular and Molecular Neuroscience

Cite this

Hales, C. M., Rees, H., Seyfried, N. T., Dammer, E. B., Duong, D. M., Gearing, M., Montine, T. J., Troncoso, J. C., Thambisetty, M., Levey, A. I., Lah, J. J., & Wingo, T. S. (2013). Abnormal Gephyrin immunoreactivity associated with Alzheimer disease pathologic changes. Journal of neuropathology and experimental neurology, 72(11), 1009-1015. https://doi.org/10.1097/01.jnen.0000435847.59828.db