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Amanda Leisgang - GABA specific changes in a mouse model of Alzheimer’s disease
Alzheimer’s disease (AD) is a progressive neurodegenerative disorder associated with learning and memory deficits, neuronal loss, and eventually death. AD is characterized by the appearance of two key pathological features. These include the accumulation of Amyloid b plaques (Ab) and hyperphosphorylated tau (ptau) that lead to neurofibrillary tangles. More recent evidence has demonstrated a sustained inflammatory response (neuroinflammation) contributes to both Ab and ptau pathology. A number of mechanisms have been proposed that are responsible for impaired learning and memory, neuroinflammation, and progressive neuronal loss including alterations in several transmitter systems. One transmitter in particular that has been loosely demonstrated to be reduced in AD clinical populations and pre-clinical models is gamma amino butyric acid (GABA). GABA is the principle inhibitory neurotransmitter in the brain and has been demonstrated to be necessary in learning and memory, largely associated with its role in coordinated oscillations within the brain. As learning and memory deficits and altered population activity have been reported in clinical AD patients and animal models of AD a more careful examination of GABAergic changes in AD progression is needed.
In order to better understand the changes in GABA as it is related to AD progression we evaluated several markers of GABAergic signaling in combination with behavioral measures and pathological markers of AD (Ab plaques and neuroinflammation) at distinct time points (4, 6, and 9 months of age) in the APP/PS1 mouse model of AD versus aged matched wild-type controls. These experiments were to determine if changes in GABA related markers precede or co-occur with the onset of AD related deficits. Our data indicate that at the time point that we observe learning and memory deficits in the APP/PS1 model and a clear presence of Ab plaque formation that protein levels of GABA receptor subunits was significantly reduced in the hippocampus. Interestingly, protein levels of GAT3 and GAD-65 were elevated at this same time point. These data indicate that while there may be a reduction GABA receptors there is an increase in mechanisms associated with GABA transport and production. These data support the need for further investigation of specific GABAergic changes in the progression of AD.