Soluble Amyloid-β 42 Stimulates Glutamate Release through Activation of the α7 Nicotinic Acetylcholine Receptor

Abstract

Alzheimer’s disease (AD) is an age-related neurodegenerative disorder characterized by progressive memory loss and hippocampal atrophy. Soluble amyloid-β (Aβ)₄₂ and plaque accumulation is implicated as the neurotoxic species in this disorder; however, at physiological concentrations (pM-nM), Aβ₄₂ contributes to neurogenesis, long-term potentiation, and neuromodulation. Because Aβ₄₂ binds the α7 nicotinic acetylcholine receptors (α7nAChRs) located presynaptically on glutamatergic terminals, involved with hippocampal dependent learning and memory, we examined the effects of the human, monomeric isoform of Aβ₄₂ 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 (50×100μm) and minimal damage to the surrounding parenchyma (50–100μm). Local application of Aβ₄₂ (0.01, 0.1, 1.0, and 10.0μM; ∼150 nl; 1-2 Seconds) elicited robust, reproducible glutamate signals in all hippocampal subfields studied. Local application of 0.1 and 1.0μM Aβ₄₂ significantly increased the average maximal amplitude of glutamate release compared to saline in the DG and CA1. 10.0μM Aβ₄₂ significantly elevated glutamate release in the DG and CA3, but not in the CA1. Glutamate release was completely attenuated with coapplication of 10.0μM α-Bungarotoxin, the potent α7nAChR antagonist. Coapplication of 10.0μM tetrodotoxin, indicates Aβ_42 - induced glutamate release originates from neuronal rather than glial sources. This study demonstrates that the human, monomeric Aβ₄₂ isoform evokes glutamate release through the α7nAChR and varies across hippocampal subfields.