Wu Z, Guo Z, Gearing M, Chen G.
Tonic inhibition in dentate gyrus impairs long-term potentiation and memory in an Alzhiemer's disease model.
Nat Commun. 2014 Jun 13;5:4159.
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To add to the discussion about mechanism, the undersigned and co-author Stanislaw Mitew would like to point out the findings of a recent study from our lab at the Wicking Centre (Mitew et al., 2013). In it, we reported no significant differences in the protein levels of GAD65/67 between wild-type and APPswe/PS1dE9 transgenics aged 12 months, but GAD activity (i.e., GABA synthesis) was significantly elevated in the cerebral cortex of the APP/PS1 mice. Furthermore, this increased activity was solely attributable to the glial fraction and not the synaptosome fractions after Percoll gradient separation of the crude synaptosome fraction from cortex. So clearly the GAD enzymes themselves are rendered more active in the presence of deposited Aβ. This would either amplify any increased-substrate effect of putrescine or glutamate accumulation, or explain higher GABA levels without requiring more substrate. The assay measures GABA production by tissue homogenates directly without differentiating between GAD65 and GAD67.
Mitew S, Kirkcaldie MT, Dickson TC, Vickers JC.
Altered synapses and gliotransmission in Alzheimer's disease and AD model mice.
Neurobiol Aging. 2013 Oct;34(10):2341-51.