Affiliations: School of Molecular and Microbial Sciences, University of Queensland, Brisbane, Australia
Correspondence:
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Corresponding author: Peter R. Dodd, School of Molecular and Microbial Sciences, University of Queensland, Brisbane 4072, Australia. Tel.: +61 7 3365 3364; Fax: +61 7 3365 469; E-mail: p.dodd@uq.edu.au.
Note: [] Communicated by Xiongwei Zhu
Abstract: Excitotoxicity may contribute to neuronal and synaptic loss in Alzheimer's disease (AD). Aberrant levels of gephyrin, a post-synaptic receptor-stabilizing protein, could affect the inhibitory modulation of excitatory impulses. We assayed gephyrin protein in two brain areas susceptible to neuronal loss in AD, and in a spared area, in autopsy tissue from normal subjects (n=15) and AD patients (n=5). Quantification was by in-gel immunodetection against known concentrations of a recombinant truncated gephyrin standard. Gephyrin abundance was significantly reduced (P < 0.01) in AD. Area-wise analysis showed that gephyrin levels were reduced in both spared and susceptible regions, indicating a global phenomenon. When samples were categorized on an index of pathological severity, gephyrin levels decreased with increasing severity until a moderate index was reached, and then increased, suggesting that higher gephyrin levels might compensate for excitotoxic damage in late stages of the disease. AD males showed a more pronounced reduction in gephyrin levels than AD females cf same-sex controls. A major splice variant of gephyrin was detected in all cases and in all three brain areas. This is the first study of gephyrin expression in AD.
Keywords: Excitotoxicity, human brain, inhibitory neurotransmission, pathogenesis, post-synaptic scaffold, protein expression, protein quantification, synaptic remodeling
