Soluble oligomers of amyloid β-protein facilitate hippocampal long-term depression by disrupting neuronal glutamate uptake

By Shaomin Li, Soyon Hong, Nina E. Shepardson, D. Walsh, G. Shankar, D. Selkoe. Neuron, 2009

909 citations recorded by the source corpus.

In Alzheimer's disease (AD), the insidious impairment of declarative memory coincides with the accumulation of extracellular amyloid-β protein (Aβ) and intraneuronal tau aggregates. Dementia severity correlates strongly with decreased synapse density in hippocampus and cortex. Although numerous studies show that soluble Aβ oligomers inhibit hippocampal long-term potentiation, their role in long-term synaptic depression (LTD) remains unclear. Here, we report that soluble Aβ oligomers from several sources (synthetic, cell culture, human brain extracts) facilitated electrically-evoked LTD in the CA1 region. Aβ-enhanced LTD was mediated by mGluR or NMDAR activity, depending on the induction protocol. Both forms of LTD were prevented by an extracellular glutamate scavenger system. Aβ-facilitated LTD was closely mimicked by the action of the glutamate reuptake inhibitor TBOA, including a shared dependence on extracellular calcium levels and activation of PP2B and GSK-3 signaling. In accord, synaptic glutamate uptake was significantly decreased by soluble Aβ. We conclude that soluble Aβ oligomers perturb synaptic plasticity by altering glutamate recycling at the synapse and promoting synapse depression.

Subfields: Cellular and Molecular Neuroscience, Cognitive Neuroscience, Physiology

View Paper: https://www.semanticscholar.org/paper/7dc36417b7bac46229b937afce8014047ba8e366

How researchers see this paper

The researchers whose trusted networks rank it highest, strongest advocate first. Every researcher gets a different order.

In Cellular and Molecular Neuroscience

1. L. Mucke
2. D. Selkoe
3. J. Palop
4. Nina E. Shepardson
5. G. Shankar
6. Shaomin Li
7. Bert J. Sakmann
8. D. Holtzman

In Cognitive Neuroscience

1. D. Selkoe
2. L. Mucke
3. G. Shankar
4. J. Palop
5. Bert J. Sakmann

In Physiology

1. L. Mucke
2. D. Selkoe
3. J. Palop
4. G. Shankar
5. Nina E. Shepardson
6. Shaomin Li
7. M. Staufenbiel
8. M. Jin

Citations in the corpus

• Molecular mechanisms of neurodegeneration in Alzheimer's disease. (2010, neutral): “A number of possibilities are under investigation, including the formation of porelike structures with channel activity (93-96); alterations in glutamate receptors and excitotoxicity (97-101); circuitry hyper-excitability (102); mitochondrial dysfunction (103, 104); lysosomal failure (105) and alter”
• Critical role of soluble amyloid-β for early hippocampal hyperactivity in a mouse model of Alzheimer’s disease (2012, background): “The downstream cellular targets that are involved in Aβ-induced neuronal hyperactivity are not entirely clear yet, but may involve elevated levels of synaptic glutamate due to reductions in synaptic glutamate uptake, as previously shown in hippocampal slices treated with Aβ dimers (30).”
• Alzheimer's disease. (2011, background): “The dimers could also facilitate long-term synaptic depression (LTD) in the hippocampus (Li et al. 2009).”
• Neurotoxicity of amyloid β-protein: synaptic and network dysfunction. (2012, background): “2009), and downstream effects on calcineurin/STEP/cofilin, p38 MAPK, and GSK-3b signaling pathways, among others (Wang et al. 2004; Shankar et al. 2007; Li et al. 2009; Tackenberg and Brandt 2009).”
• Amyloid-β Induced Neuronal Dysfunction in Alzheimer’s Disease: From Synapses toward Neural Networks (2010, background): “For example, although synthetic Aβ oligomer preparations are less potent than Aβ oligomers isolated from the supernatant of transfected cell cultures, their effects on acute hippocampal slices are qualitatively simila”
• Soluble Aβ oligomers inhibit long-term potentiation through a mechanism involving excessive activation of extrasynaptic NR2B-containing NMDA receptors (2011, methodology): “…with previous reports that increasing extracellular glutamate levels by very strong tetanic stimulation (Katagiri et al., 2001), exogenous application of low-dose NMDA (Izumi et al.,2008), or inhibition of glutamate reuptake (Katagiri et al., 2001; Li et al., 2009) can each perturb LTP induction.”