These are cutting-edge experiments building on fascinating prior work from the Klein lab showing that extracellular Aβ oligomers appear to selectively bind to excitatory synapses. The focus of the paper is mGluR5; it is quite interesting that there is differential Aβ-related lateral diffusion in and out of synapses among the synaptic receptors that they assayed. They consistently used excellent controls. The Aβ-related mGluR5 recruitment to synapses, which also occurs with LTD, is certainly interesting. A challenge is that they show many different synaptic receptors binding to Aβ42 oligomers and one is again left wondering about the relevance of any given receptor to AD. When we initiated this line of work looking for Aβ-related changes in synapses (Almeida et al., 2005), we used various antibodies against pre- and post-synaptic markers. Some changed (PSD95, glutamate receptors) while others didn’t. The challenge is to figure out which Aβ-related synapse change comes first, or is most critical. I am not sure how much headway we are...  Read more

These are cutting-edge experiments building on fascinating prior work from the Klein lab showing that extracellular Aβ oligomers appear to selectively bind to excitatory synapses. The focus of the paper is mGluR5; it is quite interesting that there is differential Aβ-related lateral diffusion in and out of synapses among the synaptic receptors that they assayed. They consistently used excellent controls. The Aβ-related mGluR5 recruitment to synapses, which also occurs with LTD, is certainly interesting. A challenge is that they show many different synaptic receptors binding to Aβ42 oligomers and one is again left wondering about the relevance of any given receptor to AD. When we initiated this line of work looking for Aβ-related changes in synapses (Almeida et al., 2005), we used various antibodies against pre- and post-synaptic markers. Some changed (PSD95, glutamate receptors) while others didn’t. The challenge is to figure out which Aβ-related synapse change comes first, or is most critical. I am not sure how much headway we are really making on this front. I will add that I also remain a bit uncertain about the relevance to AD of adding extracellular Aβ, since in my view more evidence currently points to less Aβ secretion and more intraneuronal accumulation with AD pathogenesis (Gouras et al., 2010).

View all comments by Gunnar K. Gouras

The very interesting report by Renner et al. demonstrates Aβ-induced clustering of mGluR5 receptors and suggests that membrane-bound Aβ oligomers interact with mGluR5. Since chemical crosslinking of the receptor and application of Aβ oligomers produce similar synaptotoxic effects of mGluR5, the data point to (direct or indirect) Aβ-mediated crosslinking of mGluR5 receptors and thus support the idea that Aβ can function as a receptor crosslinker (cf. Aβ-crosslinker-hypothesis).

Both mGluR5 and the neurotrophin receptor p75 influence NMDAR-dependent long-term depression elicited by low-frequency stimulation; while an mGluR5 antagonist largely prevents both induction and maintenance of LTD (e.g., Popkirov and Manahan-Vaughan, 2010), it is maintenance of LTD that is principally impaired in p75 knockout mice (Rösch et al., 2005). Modulation of mGluR5-induced LTD by p75 would agree with the crucial involvement of caspase-3 in LTD (Li et al., 2010), because stimulated p75 can induce caspase-3 activation. Modulation of mGluR5-induced...  Read more

The very interesting report by Renner et al. demonstrates Aβ-induced clustering of mGluR5 receptors and suggests that membrane-bound Aβ oligomers interact with mGluR5. Since chemical crosslinking of the receptor and application of Aβ oligomers produce similar synaptotoxic effects of mGluR5, the data point to (direct or indirect) Aβ-mediated crosslinking of mGluR5 receptors and thus support the idea that Aβ can function as a receptor crosslinker (cf. Aβ-crosslinker-hypothesis).

Both mGluR5 and the neurotrophin receptor p75 influence NMDAR-dependent long-term depression elicited by low-frequency stimulation; while an mGluR5 antagonist largely prevents both induction and maintenance of LTD (e.g., Popkirov and Manahan-Vaughan, 2010), it is maintenance of LTD that is principally impaired in p75 knockout mice (Rösch et al., 2005). Modulation of mGluR5-induced LTD by p75 would agree with the crucial involvement of caspase-3 in LTD (Li et al., 2010), because stimulated p75 can induce caspase-3 activation. Modulation of mGluR5-induced LTD also fits with a likely interaction between p75 and NMDAR via PSD-95 and an inhibitory influence of p75 on NMDAR currents (Sandoval et al., 2007), which would also protect against excitotoxicity.

P75 importantly contributes to Aβ-induced hippocampal degeneration (Sotthibundhu et al., 2008; Knowles et al., 2009), is activated by Aβ oligomers via an Aβ-binding site within its neurotrophin-binding region, and has a second binding site for Aβ within its juxtamembrane stalk region that should serve Aβ-mediated crosslinking. Although a functional cooperation of mGluR5 and p75 without direct association of the two receptors is conceivable, the idea of an Aβ-mediated interaction of mGluR5 and p75 is appealing in view of the above arguments; such an interaction could also link mGluR5 with the NMDAR complex.

References:
Knowles JK, Rajadas J, Nguyen TV, Yang T, LeMieux MC, Vander Griend L, Ishikawa C, Massa SM, Wyss-Coray T, Longo FM. (2009) The p75 neurotrophin receptor promotes amyloid-beta(1-42)-induced neuritic dystrophy in vitro and in vivo. J Neurosci 29(34):10627-37. Abstract

Li Z, Jo J, Jia JM, Lo SC, Whitcomb DJ, Jiao S, Cho K, Sheng M. (2010) Caspase-3 activation via mitochondria is required for long-term depression and AMPA receptor internalization. Cell 141(5):859-71. Abstract

Popkirov SG and Manahan-Vaughan D. (2010) Involvement of the Metabotropic Glutamate Receptor mGluR5 in NMDA Receptor-Dependent, Learning-Facilitated Long-Term Depression in CA1 Synapses. Cereb Cortex 2010 Jun 4. Abstract

Rösch H, Schweigreiter R, Bonhoeffer T, Barde YA, Korte M. (2005) The neurotrophin receptor p75NTR modulates long-term depression and regulates the expression of AMPA receptor subunits in the hippocampus. Proc Natl Acad Sci U S A 102:7362-7. Abstract

Sandoval M, Sandoval R, Thomas U, Spilker C, Smalla KH, Falcon R, Marengo JJ, Calderon R, Saavedra V, Heumann R, Bronfman F, Garner CC, Gundelfinger ED, Wyneken U. (2007) Antagonistic effects of TrkB and p75(NTR) on NMDA receptor currents in post-synaptic densities transplanted into Xenopus oocytes. J Neurochem 101:1672-84. Abstract

Sotthibundhu A, Sykes AM, Fox B, Underwood CK, Thangnipon W, Coulson, EJ. (2008) Beta-amyloid(1-42) induces neuronal death through the p75 neurotrophin receptor. J Neurosci 28:3941-6. Abstract

View all comments by Rudolf Bloechl

In this paper, it is observed that membrane-attached oligomers of amyloid-β cause clustering of metabotropic glutamate receptors (mGluR5), which leads to an increase in intracellular calcium and causes synapse deterioration. Since mGluR5 is widely distributed in brain regions crucial for memory, such as the hippocampus, this study provides an explanation for selective amyloid-β toxicity and synaptic failure in specific brain regions.

References:
Renner M, Lacor PN, Velasco PT, Xu J, Contractor A, Klein WL, Triller A. Deleterious effects of amyloid beta oligomers acting as an extracellular scaffold for mGluR5. Neuron. 2010 Jun 10;66(5):739-54. Abstract

View all comments by Mordhwaj Parihar