67 research outputs found
Genotyping of four polymorphisms potentially associated with Alzheimer's disease: A2M, APOC1, TNFa-850 AND TNFa-308
Reduced expression of the inhibitory synapse scaffolding protein gephyrin in Alzheimer's disease
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
A role for the neurexin-neuroligin complex in Alzheimer's disease
Synaptic damage is a critical hallmark of Alzheimer's disease, and the best correlate with cognitive impairment ante mortem. Synapses, the loci of communication between neurons, are characterized by signature protein combinations arrayed at tightly apposed pre- and post-synaptic sites. The most widely studied trans-synaptic junctional complexes, which direct synaptogenesis and foster the maintenance and stability of the mature terminal, are conjunctions of presynaptic neurexins and postsynaptic neuroligins. Fluctuations in the levels of neuroligins and neurexins can sway the balance between excitatory and inhibitory neurotransmission in the brain, and could lead to damage of synapses and dendrites. This review summarizes current understanding of the roles of neurexins and neuroligins proteolytic processing in synaptic plasticity in the human brain, and outlines their possible roles in β-amyloid metabolism and function, which are central pathogenic events in Alzheimer's disease progression
The quantitation of pre- and postsynaptic proteins in Alzheimer’s disease and effect of apolipoprotein E genotype
In Alzheimer's disease (AD) it has been commonly thought that cell loss would be associated with the loss of terminal inputs through retrograde degradation. Brain tissue from pathologically confirmed AD cases and controls was obtained at autopsy with written informed consent and frozen at ƒ{70„aC in 0.32 M sucrose. Areas investigated included hippocampus and inferior temporal cortex, which are susceptible to AD pathology, and occipital cortex, which is relatively spared. Levels of synaptophysin, a marker of nerve terminals, were investigated by a novel sandwich ELISA and by immunohistochemistry (IHC). N-cadherin, a marker of excitatory synapses, was analysed by immunoblotting. ELISA and cortical thickness measurements by IHC confirmed that there was no significant difference in the levels of synaptophysin between controls and AD cases, but there was a difference between areas. Immunoblotting showed slight increases in the levels of N-cadherin in all areas of AD cases compared with controls, which only reached significance in occipital cortex. There was also a significant regional difference. Cases were categorized according to Apolipoprotein E genotype by RFLP. The Apo E ƒÕ4 allele occurred at a significantly higher frequency in AD cases, and was associated with a trend toward lower synaptophysin levels in affected areas. The results suggest that terminal inputs remain intact in AD and that the risk factor Apo E4 may represent a marker of severity. Preliminary studies of other protein markers, presynaptic dynamin 1, presynaptic excitatory complexin 2 and postsynaptic ƒÑCaMKII, displayed the same regional differences. Dynamin 1 and complexin 2, involved in synaptic vesicle recycling, showed lower levels in AD cases than in controls. RKT is a Judith Mason Scholar
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