Glutamate and Dementia

Over a decade ago it was suggested by Greenamyre that glutamate might be involved in the pathomechanism of neurodegenerative diseases, like Alzheimer’s disease (Greenamyre, 1986). An important aspect of this concept is the fact that an increase in glutamate levels per se is not necessarily required, because changes in receptors sensitivity and their overactivation by resting levels of glutamate could also contribute to neuronal death (Albin & Greenamyre, 1992). Since that time, a very large amount of supportive evidence for this hypothesis has been published.

Post mortem Studies

It is most likely that glutamatergic neurons are both executors and victims of excitotoxic processes. Thus, individual synapses may show overactivity which may lead to death of postsynaptic neurons and result in a secondary hypofunction of the whole system (Francis et al., 1993).

1. Some authors have observed co-localisation of glutamatergic neurones and neurofibrillary tangles or senile plaques in the brains of AD patients (Rogers & Morrison, 1985; Pearson et al., 1985; Braak et al., 1993; Francis et al., 1993).
2. There is a decrease in the astroglial glutamate transporter EAA2 in the frontal cortex according to (Li et al., 1997) and some authors reported a correlation between a decrease in the immunoreactivity of glutamate transporter and neuronal pathology in AD patients (Masliah et al., 1996; Masliah et al., 1998).
3. High affinity platelet glutamate uptake is decreased by 40% in AD as compared to controls (Ferrarese et al., 2000).
4. In severe AD cases the intensity of NR1a (subunit of NMDA receptors) immunolabelling within the hippocampal CA3 field is increased and in the dentate gyrus there are a number of NR1-labeled plaques (Ikonomovic et al., 1999).

In Vitro

1. Cultured macrophages exposed to Aβ1-40 produce higher concentrations of glutamate and oxygen free radical and β-amyloid peptide enhances glutamate release from primary cultured rat microglia via the Na⁺-dependent glutamate transporter (Klegeris & McGeer, 1997; Noda et al., 1999).
2. In glial cultures, β-amyloid (25-35) inhibits glutamate uptake, probably connected with increased production of free radicals (Harris et al., 1995; Harris et al., 1996; Hensley et al., 1997).
3. Constituents of senile plaques stimulate microglia to produce an unknown neurotoxin (not glutamate!) with agonistic properties at NMDA receptors (Giulian et al., 1995).
4. β-amyloid peptide enhances the toxicity of glutamate (Koh et al., 1990; Mattson et al., 1992; Brorson et al., 1995).
5. Hippocampal neurons prepared from PS1 mutant knock-in mice show increased vulnerability to glutamate-induced excitotoxicity (Guo et al., 1999; Grilli et al., 2000).

In Vivo

1. Injection of β-amyloid i.c.v. produces NMDA receptor dependent, long lasting depression of EPSPs in the hippocampus which seems to be an expression of ongoing mild excitotoxicity (Cullen et al., 1996).
2. Mice, carrying mutant human preseniline-1 (PS-1) show an enhanced excitotoxic reaction to kainate (Schneider et al., 2001). Neurons isolated from these mice also show an enhanced increase in [Ca²⁺]I levels in response to glutamate (ibid.).
3. PS-1 mutant mice show enhanced sensitivity to damage induced by transient focal ischaemia (MCA occlusions) (Mattson et al., 2000).
4. Transgenic mice with an APP mutation in the a-secretase site show enhanced sensitivity to glutamatergic agonists such as kainic acid and NMDA (Moechars et al., 1996). Similar observations were seen in mutants bearing the Swedish or London mutations of APP (Moechars et al., 1999).