Amyloid Beta Oligomers-Induced Ca2+ Entry Pathways: Role of Neuronal Networks, NMDA Receptors and Amyloid Channel Formation

• Published in: Biomedicines Vol. 10; no. 5; p. 1153
• Main Authors: Caballero, Erica, Hernando-Pérez, Elena, Tapias, Victor, Calvo-Rodríguez, María, Villalobos, Carlos, Núñez, Lucía
• Format: Journal Article
• Language: English
• Published: Basel MDPI AG 17.05.2022; MDPI
• Subjects: Aging; Alzheimer's disease; amyloid β oligomers; Apoptosis; calcium; Calcium (mitochondrial); Calcium channels; Calcium channels (voltage-gated); Calcium influx; Cerebellum; Degeneration; Excitotoxicity; Glutamic acid receptors; Glutamic acid receptors (ionotropic); Hippocampus; Memory; Mitochondria; N-Methyl-D-aspartic acid receptors; Neural networks; Neurodegenerative diseases; Neurons; Oligomers; Penicillin; Peptides; Synapses; Synaptic transmission; United States > US; Madrid Spain; Spain
• ISSN: 2227-9059; 2227-9059
• DOI: 10.3390/biomedicines10051153

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.