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

The molecular basis of amyloid toxicity in Alzheimer's disease (AD) remains controversial. Amyloid β (Aβ) oligomers promote Ca influx, mitochondrial Ca overload and apoptosis in hippocampal neurons in vivo and in vitro, but the primary Ca entry pathways are unclear. We studied Ca entry pathways induced by Aβ oligomers in rat hippocampal and cerebellar neurons. Aβ oligomers induce Ca entry in neurons. Ca responses to Aβ oligomers are large after synaptic networking and prevented by blockers of synaptic transmission. In contrast, in neurons devoid of synaptic connections, Ca 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 Ca responses. Non-neuronal cells bearing NMDA receptors showed Ca responses to oligomers, whereas cells without NMDA receptors did not exhibit Ca responses. The expression of subunits of the NMDA receptor NR1/ NR2A and NR1/NR2B in HEK293 cells lacking endogenous NMDA receptors restored Ca responses to NMDA but not to Aβ oligomers. We conclude that Aβ oligomers promote Ca 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 Ca channels, leading to excitotoxicity and neuron degeneration in AD.