Reduced Expression of the Inhibitory Synapse Scaffolding Protein Gephyrin in Alzheimer's Disease

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 = 15). 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.

Reduction in Post-Synaptic Scaffolding PSD-95 and SAP-102 Protein Levels in the Alzheimer Inferior Temporal Cortex is Correlated with Disease Pathology

“…We found a loss in PSD-95 in AD ITC, but no significant loss in Hipp. Taken together, these results suggest that PSD-95 changes in AD may be dependent on both brain region and disease progression, which is consistent with documented asynchronous changes to synaptic proteins in AD [66][67][68]. Given that regions of the brain are differentially affected by AD pathology, and that the nature of disease progression means that areas affected early in the disease are significantly degenerated at end stage, greater concentrations of PSD-95 in these areas might represent compensatory mechanisms whereby surviving neurons enhance PSD-95 production in an attempt to promote dendrite outgrowth and establish new synaptic contacts with neighboring neurons.…”

Reduction in Post-Synaptic Scaffolding PSD-95 and SAP-102 Protein Levels in the Alzheimer Inferior Temporal Cortex is Correlated with Disease Pathology

“…We found a loss in PSD-95 in AD ITC, but no significant loss in Hipp. Taken together, these results suggest that PSD-95 changes in AD may be dependent on both brain region and disease progression, which is consistent with documented asynchronous changes to synaptic proteins in AD [66][67][68]. Given that regions of the brain are differentially affected by AD pathology, and that the nature of disease progression means that areas affected early in the disease are significantly degenerated at end stage, greater concentrations of PSD-95 in these areas might represent compensatory mechanisms whereby surviving neurons enhance PSD-95 production in an attempt to promote dendrite outgrowth and establish new synaptic contacts with neighboring neurons.…”

Functional excitatory to inhibitory synaptic imbalance and loss of cognitive performance in people with Alzheimer’s disease neuropathologic change

“…Whereas the amplitude of AMPA currents largely correlated with excitatory synaptic and postsynaptic density proteins, the amplitude of GABA currents did not correlate with inhibitory synaptic complexes or other inhibitory markers. This is in line with the dissociation between synaptic GABA A Rs and inhibitory postsynaptic density proteins observed in AD [1,30,47].…”

Abnormal Gephyrin Immunoreactivity Associated With Alzheimer Disease Pathologic Changes

“…Previous reports have shown reduced gephyrin expression in AD (14), although direct comparison to our study is difficult because of differences in brain homogenate preparation. The choice of Agarwal et al to use a non-detergent-extracted method with low-speed spin likely led to a reduction in the soluble protein analyzed, whereas in our work, a reduction in gephyrin expression is supported by a loss of gephyrin immunoreactivity in neuronal processes (Figure 1) and by quantitative proteomic analysis.…”

Reduction in Post-Synaptic Scaffolding PSD-95 and SAP-102 Protein Levels in the Alzheimer Inferior Temporal Cortex is Correlated with Disease Pathology

“…We found a loss in PSD-95 in AD ITC, but no significant loss in Hipp. Taken together, these results suggest that PSD-95 changes in AD may be dependent on both brain region and disease progression, which is consistent with documented asynchronous changes to synaptic proteins in AD [66][67][68]. Given that regions of the brain are differentially affected by AD pathology, and that the nature of disease progression means that areas affected early in the disease are significantly degenerated at end stage, greater concentrations of PSD-95 in these areas might represent compensatory mechanisms whereby surviving neurons enhance PSD-95 production in an attempt to promote dendrite outgrowth and establish new synaptic contacts with neighboring neurons.…”

Functional excitatory to inhibitory synaptic imbalance and loss of cognitive performance in people with Alzheimer’s disease neuropathologic change

“…Whereas the amplitude of AMPA currents largely correlated with excitatory synaptic and postsynaptic density proteins, the amplitude of GABA currents did not correlate with inhibitory synaptic complexes or other inhibitory markers. This is in line with the dissociation between synaptic GABA A Rs and inhibitory postsynaptic density proteins observed in AD [1,30,47].…”

Abnormal Gephyrin Immunoreactivity Associated With Alzheimer Disease Pathologic Changes

“…Previous reports have shown reduced gephyrin expression in AD (14), although direct comparison to our study is difficult because of differences in brain homogenate preparation. The choice of Agarwal et al to use a non-detergent-extracted method with low-speed spin likely led to a reduction in the soluble protein analyzed, whereas in our work, a reduction in gephyrin expression is supported by a loss of gephyrin immunoreactivity in neuronal processes (Figure 1) and by quantitative proteomic analysis.…”

Reduction in Post-Synaptic Scaffolding PSD-95 and SAP-102 Protein Levels in the Alzheimer Inferior Temporal Cortex is Correlated with Disease Pathology

“…We found a loss in PSD-95 in AD ITC, but no significant loss in Hipp. Taken together, these results suggest that PSD-95 changes in AD may be dependent on both brain region and disease progression, which is consistent with documented asynchronous changes to synaptic proteins in AD [66][67][68]. Given that regions of the brain are differentially affected by AD pathology, and that the nature of disease progression means that areas affected early in the disease are significantly degenerated at end stage, greater concentrations of PSD-95 in these areas might represent compensatory mechanisms whereby surviving neurons enhance PSD-95 production in an attempt to promote dendrite outgrowth and establish new synaptic contacts with neighboring neurons.…”

Functional excitatory to inhibitory synaptic imbalance and loss of cognitive performance in people with Alzheimer’s disease neuropathologic change

“…Whereas the amplitude of AMPA currents largely correlated with excitatory synaptic and postsynaptic density proteins, the amplitude of GABA currents did not correlate with inhibitory synaptic complexes or other inhibitory markers. This is in line with the dissociation between synaptic GABA A Rs and inhibitory postsynaptic density proteins observed in AD [1,30,47].…”

Abnormal Gephyrin Immunoreactivity Associated With Alzheimer Disease Pathologic Changes

“…Previous reports have shown reduced gephyrin expression in AD (14), although direct comparison to our study is difficult because of differences in brain homogenate preparation. The choice of Agarwal et al to use a non-detergent-extracted method with low-speed spin likely led to a reduction in the soluble protein analyzed, whereas in our work, a reduction in gephyrin expression is supported by a loss of gephyrin immunoreactivity in neuronal processes (Figure 1) and by quantitative proteomic analysis.…”