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Involvement of nicotinic acetylcholine receptors in amyloid β-fragment-induced intracellular Ca~(2+) elevation in cultured rat cortical neurons

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Author:: No author available

Journal Title:: ACTA PHYSIOLOGICA SINICA

Issue:: 6

DOI:: 10.3321/j.issn:0371-0874.2009.06.003

Key Word:: N型胆碱能受体;淀粉样β蛋白;皮层神经元;细胞内钙浓度;nicotinic acetylcholine receptors;amyloid P-protein;cortical neurons;intracellular calcium concentration

Abstract： The amyloid p-protein (Aβ)-induced disturbance of intracellular calcium homeostasis has been regarded as the final route whereby Ap insults neurons. However, the mechanism of Aβ-induced Ca~(2+) overloading is still unclear so far. Especially, it remains to be clarified whether nicotinic acetylcholine receptors (nAChRs) are involved in the Aβ-induced elevation of intracellular calcium concentration ([Ca~(2+)]_I). In the present study, we observed the effects of Aβ fragments 25-35 (Aβ_(25-35))and 31-35 (Aβ_(31-35)) on [Ca~(2+)]_I in primary cultured rat cortical neurons using laser-scanning confocal calcium imaging technique, and investigated its probable cholinergic mechanism. The results showed that: (1) Both Aβ_(25-35)and Aβ_(31-35) induced similar and significant ([Ca~(2+)]_I) elevation in a concentration-dependent manner, and no statistical difference was found between the effects of both peptides; (2) The reverse peptide of Aβ_(31-35), I.e. Aβ_(35-31). Had no effect on [Ca~(2+)]_I elevation; (3) Mecamylamine (MCA), a non-specific nAChRs antagonist, significantly and dose-dependently blocked the ([Ca~(2+0]_I) elevation induced by (Aβ_(25-35)) or Aβ_(31-35). (4) Dihydro-P-erythroidine (D-P-E), a specific α4β2 subtype nAChRs antagonist, also significantly inhibited the [Ca~(2+)]_I elevation induced by (Aβ_(25-35)) and Aβ_(31-35), but the effect was weaker than the effect of MCA at the same concentration. These results indicate that Aβ_(31-35) may be a shorter active sequence in full length of Aβ molecule, and the overactivation of nAChRs, including α4β2 subtype, may be, at least partly, responsible for the Aβ-induced elevation of [Ca~(2+)]_I in cultured rat cortical neurons. Thus, the present study suggests a new potential target of Aβ in the brain, and provides a new insight into the mechanisms by which Ap impairs the cognitive function in Alzheimer's disease.

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