Modulation of AMPA receptor function in relation to glutamatergic abnormalities in Alzheimer's disease

Abnormalities in the excitatory glutamate neurotransmitter system appear to be a prominent factor in Alzheimer's disease (AD). Whereas hypoactivity of this system is observed in some areas of Alzheimer brains, hyperactivity may play a role in the degenerative processes in other brain areas. This apparently paradoxical situation makes therapeutic intervention in the glutamatergic system in AD difficult and demands the development of unique therapeutic approaches. The involvement of the (RS)-2-amino-3-(3-hydroxy-5-methyl-4-isoxazolyl)propionic acid (AMPA) subtype of glutamate receptors in AD brain dysfunctions seems to be important, and compounds showing different modulatory activity at AMPA receptors are discussed in relation to therapeutic possibilities. Compounds enhancing excitatory activity at AMPA receptors may have beneficial effects on the learning and memory deficits observed in AD, whereas agents showing antagonistic or partial agonist profiles may block or delay the progressive neurodegeneration, which is a key phenomenon in AD. In vitro experiments with compounds capable of enhancing AMPA receptor activity have been performed. Such compounds without excitatory activity on their own may not show the excitotoxic properties characteristic of glutamate agonists. Another possibility for therapeutic intervention is the use of a partial agonist. The concept of "functional partial agonism" at the AMPA receptors is described with a specific example.