Abstract
Contradictory results have been reported on the interaction of beta-amyloid (Aβ) with cholinergic receptors. The present paper investigates the modulatory effect of Aβ1-40 on the neurotransmitter release evoked by nicotinic (nAChRs) and muscarinic (mAChRs) receptors. Aβ1-40 inhibits both nicotinic and muscarinic-evoked [3H]DA overflow from rat nerve endings. Added to perfusion medium, Aβ1-40 is able to enter into synaptosomes; it exerts its inhibitory effect at extracellular sites when release is stimulated by nAChRs and intracellularly when release is evoked by mAChRs. Moreover, our data show that Aβ1-40 acts as non competitive antagonist of heteromeric α4β2* but not of α3β4* nAChRs which modulate [3H]NA overflow. Positive allosteric modulators of nAChRs counteract its inhibitory effect. It might be that compounds of this type could be useful to prevent, slow down the appearance or reverse the cognitive decline typical of the normal processes of brain aging.
Highlights
The predominant clinical symptoms early associated with Alzheimer’s disease (AD) include a deficiency in memory capabilities and these deficits are linked to a selective impairment of cholinergic function (Buckingham et al, 2009; Jürgensen and Ferreira, 2010)
In presence of α-conotoxin MII (50 nM) a specific inhibitor of α6 nicotinic acetylcholine receptors (nAChRs), the 5IA85380-evoked [3H]DA overflow is significantly decreased (−44%) and further inhibited (−45%) by Aβ1-40 indicating that α-conotoxin MII—resistant nAChRs (α4- non α6) are inhibited by Aβ1-40
In order to study if the Aβ1-40 inhibitory effect on nAChRs is exerted on external or internal synaptosomal targets, we investigated whether a specific Aβ antibody present in the medium or entrapped into synaptosomes may counteract the inhibitory effect of Aβ1-40
Summary
The predominant clinical symptoms early associated with Alzheimer’s disease (AD) include a deficiency in memory capabilities and these deficits are linked to a selective impairment of cholinergic function (Buckingham et al, 2009; Jürgensen and Ferreira, 2010). It has been reported that a significant decrease in the number of α4 nicotinic acetylcholine receptors (nAChRs) is one of the earliest events in the pathogenesis of AD (Burghaus et al, 2000) even preceding cholinergic neuronal degeneration. At this regard, accumulating evidences have shown that betaamyloid (Aβ), which plays a crucial role both in the early and late phases of AD, disrupts cholinergic neurotransmission by interacting with presynaptic cholinergic receptors function (Cleary et al, 2005; Lesné et al, 2006; Mura et al, 2010a; Govoni et al, 2014). This is, for instance, the case of most nAChRs located on nerve endings, which elicit the release of several neurotransmitters in the CNS (Wonnacott, 1997)
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