Differences between GABA levels in Alzheimer's disease and Down syndrome with Alzheimer-like neuropathology

Abstract

Down syndrome (DS) is a genetic disease with developmental brain abnormalities resulting in early mental retardation and precocious, age-dependent Alzheimer-type neurodegeneration. Furthermore, non-cognitive symptoms may be a cardinal feature of functional decline in adults with DS. A number of amino acids [glutamate, aspartate, gamma-aminobutyrate (GABA), glycine, taurine, glutamine, serine, arginine] were investigated in post-mortem tissue samples from temporal, occipital cortex, thalamus, caudate nucleus, and cerebellum of adult patients with Down syndrome (DS) exhibiting Alzheimer-like neuropatholgy, Alzheimer's disease (AD) and from controls by use of high performance liquid chromatography (HPLC). In DS, no significant differences from control values could be observed in any of the brain regions. In AD, significant loss of GABA content was found in the temporal cortex (0.5+/-0.2 micromol/g vs. 1.3+/-0.8 micromol/g wet weight tissue, P<0.01), occipital cortex (0.8+/-0.2 micromol/g vs. 1.4+/-0.6 micromol/g, P<0.05) and cerebellum (1.1+/-0.3 micromol/g vs. 1.8+/-0.5 micromol/g, P<0.05). Glutamate and aspartate concentrations were significantly reduced in the caudate nucleus of AD subjects (glutamate: 6.1+/-3.4 micromol/g vs. 14.7+/-1.8 micromol/g; aspartate: 1.5+/-0.3 micromol/g vs. 3.3+/-0.4 micromol/g, P<0.05). The results of this study confirm previous findings in late stage AD and provide further information with respect to DS which may be relevant to understanding different pathogenesis of cognitive and non-cognitive (behavioral) features in DS and AD.

Potential of GABA-ergic cell therapy for schizophrenia, neuropathic pain, and Alzheimer׳s and Parkinson׳s diseases

“…This notion is supported by observations that overexpression of NPY (a neuromodulator released by a subclass of GABA-ergic neurons) in the hippocampal CA3 region, or treatment with low doses of valproate (an anti-epileptic drug that increases GABA-ergic neurotransmission), can improve hippocampal-dependent long-term memory in aged rats (Koh et al, 2010). Decreased inhibitory neurotransmission likely also occurs in AD as brain concentrations of GABA and SST are reduced in the brain and the cerebrospinal fluid (Davies et al, 1980;Hardy et al, 1987;Seidl et al, 2001). Furthermore, decreases in GABA and SST levels are more pronounced in apoE4 carriers (accounting for 60-75% of AD patients) exhibiting enhanced brain activity at rest and in response to memory tasks (Grouselle et al, 1998;Filippini et al, 2009;Dennis et al, 2010).…”

Proteomic evaluation of intermediary metabolism enzyme proteins in fetal Down's syndrome cerebral cortex

“…Decreased protein expression of cAspAT may have an effect on all these pathways. In different brain regions of adult DS patients, reduced or unchanged concentration of aspartate and glutamate has been reported [38][39][40][41]. Reduced cAspAT may account for such alterations of concentrations of the neurotransmiters aspartate and glutamate in DS brain, and a similar alteration would also be expected in fetal DS brain.…”

Apolipoprotein E: Structure and function in lipid metabolism, neurobiology, and Alzheimer's diseases

“…AD patients have decreased GABA and somatostatin levels in the brain and CSF (Bareggi et al, 1982; Davies et al, 1980; Hardy et al, 1987; Seidl et al, 2001; Zimmer et al, 1984) and these alterations were more severe in apoE4 carriers (Grouselle et al, 1998). ApoE4 is associated with increased brain activity at rest and in response to memory tasks (Dennis et al, 2009; Filippini et al, 2009), possibly reflecting impaired GABAergic inhibitory control.…”