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Amyloid Beta Oligomers-Induced Ca2+ Entry Pathways: Role of Neuronal Networks, NMDA Receptors and Amyloid Channel Formation Caballero, Erica Hernando Pérez, María Elena Tapias Molina, Victor Calvo Rodríguez, María Villalobos Jorge, Carlos Núñez Llorente, Lucía Producción Científica The molecular basis of amyloid toxicity in Alzheimer's disease (AD) remains controversial. Amyloid β (Aβ) oligomers promote Ca2+ influx, mitochondrial Ca2+ overload and apoptosis in hippocampal neurons in vivo and in vitro, but the primary Ca2+ entry pathways are unclear. We studied Ca2+ entry pathways induced by Aβ oligomers in rat hippocampal and cerebellar neurons. Aβ oligomers induce Ca2+ entry in neurons. Ca2+ responses to Aβ oligomers are large after synaptic networking and prevented by blockers of synaptic transmission. In contrast, in neurons devoid of synaptic connections, Ca2+ responses to Aβ oligomers are small and prevented only by blockers of amyloid channels (NA7) and NMDA receptors (MK801). A combination of NA7 and MK801 nearly abolished Ca2+ responses. Non-neuronal cells bearing NMDA receptors showed Ca2+ responses to oligomers, whereas cells without NMDA receptors did not exhibit Ca2+ responses. The expression of subunits of the NMDA receptor NR1/ NR2A and NR1/NR2B in HEK293 cells lacking endogenous NMDA receptors restored Ca2+ responses to NMDA but not to Aβ oligomers. We conclude that Aβ oligomers promote Ca2+ entry via amyloid channels and NMDA receptors. This may recruit distant neurons intertwisted by synaptic connections, spreading excitation and recruiting further NMDA receptors and voltage-gated Ca2+ channels, leading to excitotoxicity and neuron degeneration in AD. 2024-01-02T01:32:52Z 2024-01-02T01:32:52Z 2022 info:eu-repo/semantics/article info:eu-repo/semantics/draft Biomedicines, Mayo 2022, vol. 10, n. 5. p. 1153 https://uvadoc.uva.es/handle/10324/63898 10.3390/biomedicines10051153 1153 5 Biomedicines 10 2227-9059 eng Atribución 4.0 Internacional info:eu-repo/semantics/openAccess http://creativecommons.org/licenses/by/4.0/ application/pdf https://uvadoc.uva.es/bitstream/10324/63898/3/Caballero%20et%20al%202022_Biomedicines.pdf.jpg Hispana TEXT http://creativecommons.org/licenses/by/4.0/ UVaDOC. Repositorio Documental de la Universidad de Valladolid https://uvadoc.uva.es/handle/10324/63898