Amyloid β-Peptide Oligomers Stimulate RyR-Mediated Ca²⁺ Release Inducing Mitochondrial Fragmentation in Hippocampal Neurons and Prevent RyR-Mediated Dendritic Spine Remodeling Produced by BDNF

Abstract

Soluble amyloid β-peptide oligomers (AβOs), increasingly recognized as causative agents of Alzheimer's disease (AD), disrupt neuronal Ca(2+) homeostasis and synaptic function. Here, we report that AβOs at sublethal concentrations generate prolonged Ca(2+) signals in primary hippocampal neurons; incubation in Ca(2+)-free solutions, inhibition of ryanodine receptors (RyRs) or N-methyl-d-aspartate receptors (NMDARs), or preincubation with N-acetyl-l-cysteine abolished these signals. AβOs decreased (6 h) RyR2 and RyR3 mRNA and RyR2 protein, and promoted mitochondrial fragmentation after 24 h. NMDAR inhibition abolished the RyR2 decrease, whereas RyR inhibition prevented significantly the RyR2 protein decrease and mitochondrial fragmentation induced by AβOs. Incubation with AβOs (6 h) eliminated the RyR2 increase induced by brain-derived nerve factor (BDNF) and the dendritic spine remodeling induced within minutes by BDNF or the RyR agonist caffeine. Addition of BDNF to neurons incubated with AβOs for 24 h, which had RyR2 similar to and slightly higher RyR3 protein content than those of controls, induced dendritic spine growth but at slower rates than in controls. These combined effects of sublethal AβOs concentrations (which include redox-sensitive stimulation of RyR-mediated Ca(2+) release, decreased RyR2 protein expression, mitochondrial fragmentation, and prevention of RyR-mediated spine remodeling) may contribute to impairing the synaptic plasticity in AD.

Involvement of ryanodine receptors in neurotrophin-induced hippocampal synaptic plasticity and spatial memory formation

“…Accordingly, incubation of hippocampal cultures with 1 μM ryanodine stimulates Ca 2+ release (Fig. S3A), whereas prolonged incubation with 50 μM ryanodine suppresses it (18,25). Here, we show that cultures preincubated with inhibitory ryanodine (50 μM, 1 h) did not exhibit the above changes in RyR2, RyR3, and PKMζ mRNA, and protein contents produced by 6 h incubation with BDNF ( Fig.…”

Reversible epigenetic histone modifications and Bdnf expression in neurons with aging and from a mouse model of Alzheimer’s disease

“…Immunoblots with 6E10 antibody demonstrate the presence of oligomers in our preparation as well as fibers by staining with thioflavin S (data not shown; Paula-Lima et al 2011). Cells adhered to slips were returned to the incubator overnight.…”

Alzheimer’s disease and insulin resistance: translating basic science into clinical applications

“…Interestingly, Aβ oligomer-induced neuronal oxidative stress (53,54,74) is blocked by insulin (16,75). The mechanism of protection by insulin appears to involve activation of AKT (75) and prevention of abnormal NMDA receptor (NMDA-R) activation (76).…”

“…NMDA-R dysfunction indeed seems to play a role in oxidative stress and defective neuronal insulin signaling in AD, as Aβ oligomer-induced inhibition of IR signaling is prevented by the NMDA-R blocker memantine (15). Memantine and an anti-NMDA-R antibody further attenuate the oligomer-induced increase in intraneuronal calcium, which is essential in causing neuronal oxidative stress (53,74). A mechanism involving aberrant calcium influx and oxidative stress may underlie insulin resistance in AD, as glutamate and neuronal depolarization reduce the responsiveness of IRs to insulin (15), and chelation of intracellular calcium with BAPTA-AM prevents both oligomer-induced IR inhibition (15) and oxidative stress (53).…”