Protein misfolding is implicated in different severe amyloid-related neurodegenerative diseases, like Alzheimer's, Parkinson’s and Creutzfeldt-Jacob’s. This process results in the aggregation of toxic small soluble prefibrillar oligomers (PFOs), almost ineffective proto-fibrils (PFs) and mature fibres (MFs). Many efforts are pointing to clarify PFOs structures and cytotoxicity. However, since their metastability, oligomers change their conformation along with the experiments leading to inconsistency in comparing data from different groups. Salmon Calcitonin (sCT), is a 32 amino acid polypeptide hormone displaying the tendency to self-assemble in the amyloid pattern, with a very low aggregation rate. This appealing feature allows investigating the effects of native PFOs in the early stages of neurotoxicity, without any chemical stabilization. We purified sCT PFOs enriched fractions by means of size exclusion chromatography (SEC) aiming to find who is the most toxic species, among sCT PFOs, comparing the biologic effects of native PFOs enriched fraction respect to sCT monomers. The intracellular Ca2+ rise plays a fundamental role in amyloid protein-induced neurodegenerations. According to what we found in literature, two paradigms have been explored: i) the “membrane permeabilization” due to the formation of amyloid pores or other types of membrane damage; ii) “receptor-mediated” modulation of Ca2+ channels. Therefore, we tested the effects of native sCT PFOs or monomers in differentiated neurons, employing Ca2+imaging, cellular viability, Long-Term Potentiation (LTP), post-synaptic densities protein expression, excised patch-clamp recordings, and miniature-Excitatory Post-Synaptic Currents (mEPSC). Results indicated that PFOs-, but not Monomer-enriched solutions, induced abnormal permeability to Ca2+, not fully explained by N-methyl-D-aspartate receptors (NMDARs) activation. We also found that the formation of small amyloid pores was consistent with an increased quantal release of neurotransmitters, able to drive a receptor-mediated response, per se. Thus, we propose an innovative neurotoxicity mechanism for amyloid proteins where the “membrane permeabilization” and “receptor-mediated” paradigms coexist.