Differential modulation of alpha 7 nicotinic achrs by picomolar vs. high nanomolar or micromolar concentrations of amyloid beta 42 peptide.

Abstract

High concentrations (0.1-1.0 μM) of soluble oligomeric amyloid beta peptide(s) [Aβ] inhibit activation of α7 nAChRs. This may contribute to Alzheimer's Disease (AD) neuropathology, since α7 Rs play important roles in learning and memory. Thus, α7 Rs may be important targets for attenuating Aβ-induced AD cognitive declines. In contrast to the synapto-/neuro-toxic effects of high Aβ concentration observed in AD brains, several studies suggest that the low (pM) Aβ concentrations present in healthy non-AD brains are critical for normal learning and memory. These beneficial effects are dependent on expression of α7, suggesting that pM Aβ's salutary effects are mediated by α7 Rs, possibly as an agonist or PAM at α7 Rs. The nature of the Aβ-α7 R interaction, however, has not been fully characterized. In this study we found that 10-100 pM Aβ produced a ∼1.7- to 2.6-fold facilitation of ACh-elicited α7 currents, but did not elicit α7 currents directly. When applied with the type II PAM PNU 120596, 100 pM Aβ occluded the facilitation of peak current produced by PNU 120596, suggesting that Aβ and PNU 120596 potentiated α7 Rs through the same or overlapping allosteric site(s). This conclusion was further supported by analysis of a mutant α7 R containing a missense mutation in a critical amino acid for potentiation by PAMs (M276L in TM 2). Peak current facilitation by 100 pM Aβ was abolished for this mutant. Surprisingly, this mutation also abolished the inhibitory effects of high (0.1-1.0 μM) Aβ concentrations. This suggests that inhibitory (nM to µM) and facilitatory (pM) Aβ concentrations exert their opposing effects on α7 R activity via the same or overlapping sites, rather than at distinct allosteric sites.