Soluble Amyloid-β42 Stimulates Glutamate Release through Activation of the α7 Nicotinic Acetylcholine Receptor

Alzheimer's disease (AD) is an age-related neurodegenerative disorder characterized by progressive memory loss and hippocampal atrophy. Soluble amyloid-beta (A beta)(42) and plaque accumulation is implicated as the neurotoxic species in this disorder; however, at physiological concentrations (pM-nM), A beta(42) contributes to neurogenesis, long-term potentiation, and neuromodulation. Because A beta(42) binds the alpha 7 nicotinic acetylcholine receptors (alpha 7nAChRs) located presynaptically on glutamatergic terminals, involved with hippocampal dependent learning and memory, we examined the effects of the human, monomeric isoform of A beta(42) on glutamate release in the dentate gyrus (DG), CA3, and CA1, of isoflurane anesthetized, 6-9 month old male C57BL/6J mice. We utilized an enzyme-based microelectrode array selective for L-glutamate measures with fast temporal (4 Hz), low spatial resolution (50x100 mu m) and minimal damage to the surrounding parenchyma (50-100 mu m). Local application of A beta(42) (0.01, 0.1, 1.0, and 10.0 mu M; similar to 150 nl; 1-2 Seconds) elicited robust, reproducible glutamate signals in all hippocampal subfields studied. Local application of 0.1 and 1.0 mu M A beta(42) significantly increased the average maximal amplitude of glutamate release compared to saline in the DG and CA1. 10.0 mu M A beta(42) significantly elevated glutamate release in the DG and CA3, but not in the CA1. Glutamate release was completely attenuated with coapplication of 10.0 mu M alpha-Bungarotoxin, the potent alpha 7nAChR antagonist. Coapplication of 10.0 mu M tetrodotoxin, indicates A beta(42)-induced glutamate release originates from neuronal rather than glial sources. This study demonstrates that the human, monomeric A beta(42) isoform evokes glutamate release through the alpha 7nAChR and varies across hippocampal subfields.