Effects of soluble β-amyloid on the release of neurotransmitters from rat brain synaptosomes

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.

Selective co-activation of α7- and α4β2-nicotinic acetylcholine receptors reverses beta-amyloid-induced synaptic dysfunction

“…In line with this idea, our previous work demonstrates that Aβ induces neuronal hyperexcitation, an important characteristic in AD linked to network hyperexcitability and consequential dysfunction in brain rhythms (5), in cultured hippocampal excitatory neurons by predominantly reducing neuronal activity in inhibitory neurons via selective inhibition of α7-and α4β2-nAChRs, but not α3β4-nAChRs (32). Consistent with these findings, considerable evidence suggests that Aβ exerts subtype-specific inhibition of α7-and/or α4β2-nAChR function without affecting α3β4-nAChRs (21)(22)(23)32,(35)(36)(37)(38)(39). The expression of α7 and α4 subtypes is also more significantly reduced in the cortex and hippocampus of AD patients compared to α3-type receptors (40,41).…”

Selective coactivation of α7- and α4β2-nicotinic acetylcholine receptors reverses beta-amyloid–induced synaptic dysfunction

“…In line with this idea, our previous work demonstrates that Aβ induces neuronal hyperexcitation, an important characteristic in AD linked to network hyperexcitability and consequential dysfunction in brain rhythms ( 5 ), in cultured hippocampal excitatory neurons by predominantly reducing neuronal activity in inhibitory neurons via selective inhibition of α7- and α4β2-nAChRs, but not α3β4-nAChRs ( 32 ). Consistent with these findings, considerable evidence suggests that Aβ exerts subtype-specific inhibition of α7- and/or α4β2-nAChR function without affecting α3β4-nAChRs ( 21 , 22 , 23 , 32 , 35 , 36 , 37 , 38 , 39 ). The expression of α7 and α4 subtypes is also more significantly reduced in the cortex and hippocampus of patients with AD compared with α3-type receptors ( 40 , 41 ).…”

Role of the nicotinic acetylcholine receptor in Alzheimer's disease pathology and treatment

“…In this case, a distinct response of homomeric and heteromeric receptors was found, specifically, α7 are activated at pM concentrations of Aß, while non-α7 receptors were responsive at nM Aß concentrations (Dougherty et al, 2003). A study performed on nerve endings with application of Aß demonstrated a non competitive action of Aß 1-40 on α4ß2 nAChR (Olivero et al, 2014).…”