RT info:eu-repo/semantics/article
T1 Amyloid Beta Oligomers-Induced Ca2+ Entry Pathways: Role of Neuronal Networks, NMDA Receptors and Amyloid Channel Formation
A1 Caballero, Erica
A1 Hernando-Pérez, Elena
A1 Tapias, Victor
A1 Calvo-Rodríguez, María
A1 Villalobos, Carlos
A1 Núñez, Lucía
AB 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.
YR 2022
FD 2022
LK https://uvadoc.uva.es/handle/10324/63898
UL https://uvadoc.uva.es/handle/10324/63898
LA eng
NO Biomedicines, Mayo 2022, vol. 10, n. 5. p. 1153
NO Producción Científica
DS UVaDOC
RD 12-jul-2024