Natural Oligomers of the Alzheimer Amyloid-β Protein Induce Reversible Synapse Loss by Modulating an NMDA-Type Glutamate Receptor-Dependent Signaling Pathway
By G. Shankar, Brenda L. Bloodgood, Matthew Townsend, D. Walsh, D. Selkoe, Bernardo L. Sabatini. Journal of Neuroscience, 2007
1,641 citations recorded by the source corpus.
Alzheimer's disease (AD) is characterized by decreased synapse density in hippocampus and neocortex, and synapse loss is the strongest anatomical correlate of the degree of clinical impairment. Although considerable evidence supports a causal role for the amyloid-β protein (Aβ) in AD, a direct link between a specific form of Aβ and synapse loss has not been established. We demonstrate that physiological concentrations of naturally secreted Aβ dimers and trimers, but not monomers, induce progressive loss of hippocampal synapses. Pyramidal neurons in rat organotypic slices had markedly decreased density of dendritic spines and numbers of electrophysiologically active synapses after exposure to picomolar levels of soluble oligomers. Spine loss was reversible and was prevented by Aβ-specific antibodies or a small-molecule modulator of Aβ aggregation. Mechanistically, Aβ-mediated spine loss required activity of NMDA-type glutamate receptors (NMDARs) and occurred through a pathway involving cofilin and calcineurin. Furthermore, NMDAR-mediated calcium influx into active spines was reduced by Aβ oligomers. Partial blockade of NMDARs by pharmacological antagonists was sufficient to trigger spine loss. We conclude that soluble, low-n oligomers of human Aβ trigger synapse loss that can be reversed by therapeutic agents. Our approach provides a quantitative cellular model for elucidating the molecular basis of Aβ-induced neuronal dysfunction.
Subfields: Cellular and Molecular Neuroscience, Pharmacology, Physiology
View Paper: https://www.semanticscholar.org/paper/013b120f2f50d0dc614e533dc73631288c33973b
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Citations in the corpus
- Apolipoprotein E and apolipoprotein E receptors: normal biology and roles in Alzheimer disease. (2012, background): “Synaptic suppression by the oligomers correlates with reduced NMDA receptor activity (Snyder et al. 2005; Shankar et al. 2007), which is caused by NMDA receptor dephosphorylation and accelerated endocytosis (Snyder et al. 2005).”
- The Amyloid-β Oligomer Hypothesis: Beginning of the Third Decade (2018, background): “Overall, A Os have been found to instigate tau pathology [19, 51, 52], loss of neuronal polarity [53–55], impairment of axonal transport [56–58], deterioration of synapses [47, 55], oxidative stress [59–62], endoplasmic reticulum (ER) stress [18, 63, 64], insulin resistance [48, 65–67], neuroinflamm”
- Aberrant excitatory neuronal activity and compensatory remodeling of inhibitory hippocampal circuits in mouse models of Alzheimer's disease. (2007, neutral): “…data are consistent with the growing literature suggesting that A b induces impairments in synaptic glutamatergic transmission and retraction of excitatory dendritic spines (Hsia et al., 1999; Hsieh et al., 2006; Kamenetz et al., 2003; Palop et al., 2005; Shankar et al., 2007; Walsh et al., 2002).”
- Alzheimer Disease: An Update on Pathobiology and Treatment Strategies (2019, positive): “Soluble oligomers isolated from AD brain have been shown to potently inhibit long-term potentiation (LTP), enhance long-term depression (LTD) and reduce dendritic spine density in rodent hippocampal slice cultures (Kamenetz et al., 2003; Shankar et al., 2007; Wei et al., 2010).”
- Soluble Aβ oligomers inhibit long-term potentiation through a mechanism involving excessive activation of extrasynaptic NR2B-containing NMDA receptors (2011, background): “We have no evidence that the soluble A oligomers bind directly to NR2B, to other NMDAR subunits, or indeed to any specific hydrophilic cell surface receptor, as discussed previously (Shankar et al., 2007, their Fig.”
- Role of glutamate and NMDA receptors in Alzheimer’s disease (2016, positive): “The structural effects of A (cid:2) , such as synaptic loss, can also be prevented by NMDAR antagonists [49, 50].”
- Imbalance between GABAergic and Glutamatergic Transmission Impairs Adult Neurogenesis in an Animal Model of Alzheimer’s Disease (2009, positive): “…hippocampal neurons or organotypic hippocampal slice cultures, Ab reduces glutamatergic neurotransmission by enhancing the endocytosis of NMDA- and AMPA-type glutamate receptors, which requires the activation of calcineurin (Hsieh et al., 2006; Shankar et al., 2007; Snyder et al., 2005a).”
- Amyloid-β Induced Neuronal Dysfunction in Alzheimer’s Disease: From Synapses toward Neural Networks (2010, background): “and that elevated Aβ attenuates excitatory synaptic transmission by decreasing the number of surface AMPA receptors (AMPARs) and NMDA receptors (NMDARs), associated with a collapse of glutamatergic dendritic spine”
- Amyloid β-based therapy for Alzheimer’s disease: challenges, successes and future (2023, background): “Aβ oligomers also regulated the trafficking of NMDARs to change dendritic spine density.(222,227,229) As with NMDARs, AMPARs are also the principal receptors mediating excitatory synaptic transmission.”
- Aβ plaques lead to aberrant regulation of calcium homeostasis in vivo resulting in structural and functional disruption of neuronal networks (2008, positive): “We postulated that a moderate rise in intracellular calcium would be sufficient to activate CaN (Shankar et al., 2007; Wen et al., 2004)—in certain conditions, increased CaN activity has been shown to lead to neurite degeneration and, more specifically, neuritic beading (Zeng et al.”