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.

Ryanodine receptors (RyR) amplify activity-dependent calcium influx via calcium-induced calcium release. Calcium signals trigger postsynaptic pathways in hippocampal neurons that underlie synaptic plasticity, learning, and memory. Recent evidence supports a role of the RyR2 and RyR3 isoforms in these processes. Along with calcium signals, brain-derived neurotrophic factor (BDNF) is a key signaling molecule for hippocampal synaptic plasticity and spatial memory. Upon binding to specific TrkB receptors, BDNF initiates complex signaling pathways that modify synaptic structure and function. Here, we show that BDNF-induced remodeling of hippocampal dendritic spines required functional RyR. Additionally, incubation with BDNF enhanced the expression of RyR2, RyR3, and PKMζ, an atypical protein kinase C isoform with key roles in hippocampal memory consolidation. Consistent with their increased RyR protein content, BDNF-treated neurons generated larger RyR-mediated calcium signals than controls. Selective inhibition of RyR-mediated calcium release with inhibitory ryanodine concentrations prevented the PKMζ, RyR2, and RyR3 protein content enhancement induced by BDNF. Intrahippocampal injection of BDNF or training rats in a spatial memory task enhanced PKMζ, RyR2, RyR3, and BDNF hippocampal protein content, while injection of ryanodine at concentrations that stimulate RyR-mediated calcium release improved spatial memory learning and enhanced memory consolidation. We propose that RyR-generated calcium signals are key features of the complex neuronal plasticity processes induced by BDNF, which include increased expression of RyR2, RyR3, and PKMζ and the spine remodeling required for spatial memory formation.dendritic spine remodeling | Morris water maze | endoplasmic reticulum | protein expression

Alzheimer′s disease (AD) is the most common form of dementia in the elderly. Memory loss in AD is increasingly attributed to soluble oligomers of the amyloid-b peptide (AbOs), toxins that accumulate in AD brains and target particular synapses. Glutamate receptors appear to be centrally involved in synaptic targeting by AbOs. Once bound to neurons, AbOs dysregulate the activity and reduce the surface expression of both N-methyl-D-aspartate (NMDA) and 2-amino-3-(3-hydroxy-5-methyl-isoxazol-4-yl)propanoic acid (AMPA) types of glutamate receptors, impairing signaling pathways involved in synaptic plasticity. In the extracellular milieu, AbOs promote accumulation of the excitatory amino acids, glutamate and D-serine. This leads to overactivation of glutamate receptors, triggering abnormal calcium signals with noxious impacts on neurons. Here, we review key findings linking AbOs to deregulated glutamate neurotransmission and implicating this as a primary mechanism of synapse failure in AD. We also discuss strategies to counteract the impact of AbOs on excitatory neurotransmission. In particular, we review evidence showing that inducing neuronal hyperpolarization via activation of inhibitory GABA A receptors prevents AbOinduced excitotoxicity, suggesting that this could comprise a possible therapeutic approach in AD.

Background: Soluble A␤ oligomers (A␤Os) have been increasingly proposed as the cause of synapse failure and cognitive dysfunction in Alzheimer disease. Results: Sublethal A␤O concentrations induce changes in gene expression in adult human brain slices. Conclusion: A␤Os impact transcription in important neuronal pathways preceding neurodegeneration. Significance: Results establish early mechanisms involved in A␤O-triggered neuronal dysfunction in a novel human-derived experimental model.

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Soluble oligomers of the amyloid-β peptide (AβOs) accumulate in Alzheimer's disease (AD) brain and have been implicated in mechanisms of pathogenesis. The neurotoxicity of AβOs appears to be, at least in part, due to dysregulation of glutamate signaling. Here, we show that AβOs promote extracellular accumulation of glutamate and d-serine, a co-agonist at glutamate receptors of the N-methyl-d-aspartate subtype (NMDARs), in hippocampal neuronal cultures. The increase in extracellular glutamate levels induced by AβOs was blocked by the sodium channel blocker tetrodotoxin (TTX), by the NMDAR blocker (+)-5-methyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5,10-imine maleate (MK-801) and by removal of Ca(2+) from the extracellular medium, indicating dependence on excitatory neuronal activity. AβOs enhanced both the release of pre-synaptic vesicles labeled by FM1-43 and spontaneous post-synaptic activity measured by whole-cell patch-clamp. Activation of inhibitory GABA(A) receptors by taurine blocked the increase in extracellular glutamate levels, suggesting that selective pharmacological inhibition of neuronal activity can counteract the impact of AbOs on glutamate dyshomeostasis. Results reveal a novel mechanism by which Ab oligomers promote abnormal release of glutamate in hippocampal neurons, which may contribute to dysregulation of excitatory signaling in the brain.

Based on these combined results, we propose (i) that BDNF-induced RyR2-mediated Ca release and ROS generation via NOS/NOX2 are strictly required for the dendritic spine remodeling and the RyR2 upregulation induced by BDNF, and (ii) that RyR2 channel expression is crucial for spatial memory processes. Antioxid. Redox Signal. 29, 1125-1146.