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

Abstract

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.

Keywords: Alzheimer’s disease; amyloid β oligomers; calcium.