Smith LM, Kostylev MA, Lee S, Strittmatter SM.
Systematic and standardized comparison of reported amyloid-β receptors for sufficiency, affinity, and Alzheimer's disease relevance.
J Biol Chem. 2019 Apr 12;294(15):6042-6053. Epub 2019 Feb 20
PubMed.
This paper is a much-needed quantitative examination of which proteins are necessary and sufficient to constitute Aβ 42 oligomer receptors.
Oligomers as ligands
Beginning more than 20 years ago (Lambert et al., 1998), Aβ42 oligomers are thought to be responsible for Alzheimer’s disease, yet defining their biology has been hampered by the fact that they are challenging to handle and quantify, leading to a published literature that the authors diplomatically refer to as “highly disparate in both the quality and nature of evidence.” Uncritical reviews of this literature do little to dispel the perception that oligomers are just “sticky junk” and simply add to the noise and confusion in the field. The stakes are quite high: If oligomers are ligands that bind specifically and saturably to a single receptor site on neurons, then Alzheimer’s disease might be explained by the principles of mass action (ligand-receptor, or “lock and key” mechanisms), and therapeutics are historically quite effective in this context. This would represent very good news for millions of Alzheimer’s patients and their families. Moreover, Aβ42 polydisperse oligomers (i.e., they exist in a range of sizes, including trimers, tetramers, dodecamers, etc.) are not the only disease-relevant polydisperse oligomers that behave as ligands.
That evolution can produce a disease-specific protein ligand that is polydisperse but which nevertheless contains a single epitope (or multiple copies of this single epitope) that binds specifically and saturably to a single receptor site is certainly possible. Biologists have never dealt with polydisperse disease-causing ligands before, and new approaches would be required. That synthetic oligomer preparations made under different conditions can lead to different structures, and the fact that a quantitatively precise relationship between these synthetic structures and species found in the AD patient’s brain has not yet been defined, only add to the challenges. That all synthetic preparations of this polydisperse ligand exist in equilibrium with substantial concentrations of monomer complicates the challenge of defining biology resulting from each.
The solution to deconvoluting this complexity is to study oligomer biology using side-by-side comparison of different synthetic oligomeric preps, and including in this comparison oligomers derived from human AD patients (the most disease-relevant) and age-matched cognitively normal controls. Unfortunately, all too few publications have done so (Reed et al., 2011; Izzo et al., 2014). This paper is a much-needed addition to that literature.
Defining specific oligomer receptors
An essential part of understanding oligomer biology is to define the proteins participating in the single receptor site to which this polydisperse ligand binds saturably and specifically. It has been quite some time since neuroscientists had to consider the criteria by which a particular protein is formally designated as a receptor; most major radioligand-binding sites in the brain were defined as corresponding to particular proteins many decades ago. The authors carefully consider criteria of necessity and sufficiency for nomination of a protein to receptor status, a key feature of such a definition.
As the authors pointed out, it is possible that co-receptors may be missing in the heterologous cell lines they used to measure binding; this might change the status of some of the receptors they ruled out as mediating Aβ42 oligomer binding. The disease itself occurs in the neurons and glia of the brain, cell types which have significant differences from tumor cell lines with respect to cell surface protein expression and downstream signaling pathways, most notably related to neurotransmission and synaptic plasticity. Examining these interactions in brain cell populations is the “gold standard” for defining disease-relevant oligomer receptors. However, the author’s results in hippocampal neurons replicate the COS-7 cell work indicating that PrPc, NgR1, and LilrB2 are oligomer receptors. Most intriguingly, together these proteins only account for 70 percent of oligomer binding to neurons, suggesting that at least one additional protein participates in this receptor complex.
One additional note: while we (Izzo et al., 2014; Izzo et al., 2014) are frequently misquoted as saying that the sigma-2 receptor complex and its tightly associated protein PGRMC1 is an oligomer receptor, our 2014 paper states that the evidence indicates that this protein complex regulates the oligomer receptor complex, and is critical for doing so (Izzo et al., 2014). Our evidence suggests that sigma-2 antagonists destabilize the receptor binding site and increase the off-rate of oligomer binding, rather than competing directly with oligomers for access to the binding site (and in fact it is unlikely that small-molecule ligands are capable of directly blocking protein-protein interactions). Our drug CT1812 (ElaytaTM) is thus properly referred to as a sigma-2 receptor antagonist (Grundman et al., 2019), and is currently in clinical trials in AD patients.
References:
Izzo NJ, Staniszewski A, To L, Fa M, Teich AF, Saeed F, Wostein H, Walko T 3rd, Vaswani A, Wardius M, Syed Z, Ravenscroft J, Mozzoni K, Silky C, Rehak C, Yurko R, Finn P, Look G, Rishton G, Safferstein H, Miller M, Johanson C, Stopa E, Windisch M, Hutter-Paier B, Shamloo M, Arancio O, LeVine H 3rd, Catalano SM.
Alzheimer's therapeutics targeting amyloid beta 1-42 oligomers I: Abeta 42 oligomer binding to specific neuronal receptors is displaced by drug candidates that improve cognitive deficits.
PLoS One. 2014;9(11):e111898. Epub 2014 Nov 12
PubMed.
Izzo NJ, Xu J, Zeng C, Kirk MJ, Mozzoni K, Silky C, Rehak C, Yurko R, Look G, Rishton G, Safferstein H, Cruchaga C, Goate A, Cahill MA, Arancio O, Mach RH, Craven R, Head E, LeVine H 3rd, Spires-Jones TL, Catalano SM.
Alzheimer's therapeutics targeting amyloid beta 1-42 oligomers II: Sigma-2/PGRMC1 receptors mediate Abeta 42 oligomer binding and synaptotoxicity.
PLoS One. 2014;9(11):e111899. Epub 2014 Nov 12
PubMed.
Lambert MP, Barlow AK, Chromy BA, Edwards C, Freed R, Liosatos M, Morgan TE, Rozovsky I, Trommer B, Viola KL, Wals P, Zhang C, Finch CE, Krafft GA, Klein WL.
Diffusible, nonfibrillar ligands derived from Abeta1-42 are potent central nervous system neurotoxins.
Proc Natl Acad Sci U S A. 1998 May 26;95(11):6448-53.
PubMed.
Comments
Cognition Therapeutics Inc.
This paper is a much-needed quantitative examination of which proteins are necessary and sufficient to constitute Aβ 42 oligomer receptors.
Oligomers as ligands
Beginning more than 20 years ago (Lambert et al., 1998), Aβ42 oligomers are thought to be responsible for Alzheimer’s disease, yet defining their biology has been hampered by the fact that they are challenging to handle and quantify, leading to a published literature that the authors diplomatically refer to as “highly disparate in both the quality and nature of evidence.” Uncritical reviews of this literature do little to dispel the perception that oligomers are just “sticky junk” and simply add to the noise and confusion in the field. The stakes are quite high: If oligomers are ligands that bind specifically and saturably to a single receptor site on neurons, then Alzheimer’s disease might be explained by the principles of mass action (ligand-receptor, or “lock and key” mechanisms), and therapeutics are historically quite effective in this context. This would represent very good news for millions of Alzheimer’s patients and their families. Moreover, Aβ42 polydisperse oligomers (i.e., they exist in a range of sizes, including trimers, tetramers, dodecamers, etc.) are not the only disease-relevant polydisperse oligomers that behave as ligands.
That evolution can produce a disease-specific protein ligand that is polydisperse but which nevertheless contains a single epitope (or multiple copies of this single epitope) that binds specifically and saturably to a single receptor site is certainly possible. Biologists have never dealt with polydisperse disease-causing ligands before, and new approaches would be required. That synthetic oligomer preparations made under different conditions can lead to different structures, and the fact that a quantitatively precise relationship between these synthetic structures and species found in the AD patient’s brain has not yet been defined, only add to the challenges. That all synthetic preparations of this polydisperse ligand exist in equilibrium with substantial concentrations of monomer complicates the challenge of defining biology resulting from each.
The solution to deconvoluting this complexity is to study oligomer biology using side-by-side comparison of different synthetic oligomeric preps, and including in this comparison oligomers derived from human AD patients (the most disease-relevant) and age-matched cognitively normal controls. Unfortunately, all too few publications have done so (Reed et al., 2011; Izzo et al., 2014). This paper is a much-needed addition to that literature.
Defining specific oligomer receptors
An essential part of understanding oligomer biology is to define the proteins participating in the single receptor site to which this polydisperse ligand binds saturably and specifically. It has been quite some time since neuroscientists had to consider the criteria by which a particular protein is formally designated as a receptor; most major radioligand-binding sites in the brain were defined as corresponding to particular proteins many decades ago. The authors carefully consider criteria of necessity and sufficiency for nomination of a protein to receptor status, a key feature of such a definition.
As the authors pointed out, it is possible that co-receptors may be missing in the heterologous cell lines they used to measure binding; this might change the status of some of the receptors they ruled out as mediating Aβ42 oligomer binding. The disease itself occurs in the neurons and glia of the brain, cell types which have significant differences from tumor cell lines with respect to cell surface protein expression and downstream signaling pathways, most notably related to neurotransmission and synaptic plasticity. Examining these interactions in brain cell populations is the “gold standard” for defining disease-relevant oligomer receptors. However, the author’s results in hippocampal neurons replicate the COS-7 cell work indicating that PrPc, NgR1, and LilrB2 are oligomer receptors. Most intriguingly, together these proteins only account for 70 percent of oligomer binding to neurons, suggesting that at least one additional protein participates in this receptor complex.
One additional note: while we (Izzo et al., 2014; Izzo et al., 2014) are frequently misquoted as saying that the sigma-2 receptor complex and its tightly associated protein PGRMC1 is an oligomer receptor, our 2014 paper states that the evidence indicates that this protein complex regulates the oligomer receptor complex, and is critical for doing so (Izzo et al., 2014). Our evidence suggests that sigma-2 antagonists destabilize the receptor binding site and increase the off-rate of oligomer binding, rather than competing directly with oligomers for access to the binding site (and in fact it is unlikely that small-molecule ligands are capable of directly blocking protein-protein interactions). Our drug CT1812 (ElaytaTM) is thus properly referred to as a sigma-2 receptor antagonist (Grundman et al., 2019), and is currently in clinical trials in AD patients.
References:
Izzo NJ, Staniszewski A, To L, Fa M, Teich AF, Saeed F, Wostein H, Walko T 3rd, Vaswani A, Wardius M, Syed Z, Ravenscroft J, Mozzoni K, Silky C, Rehak C, Yurko R, Finn P, Look G, Rishton G, Safferstein H, Miller M, Johanson C, Stopa E, Windisch M, Hutter-Paier B, Shamloo M, Arancio O, LeVine H 3rd, Catalano SM. Alzheimer's therapeutics targeting amyloid beta 1-42 oligomers I: Abeta 42 oligomer binding to specific neuronal receptors is displaced by drug candidates that improve cognitive deficits. PLoS One. 2014;9(11):e111898. Epub 2014 Nov 12 PubMed.
Izzo NJ, Xu J, Zeng C, Kirk MJ, Mozzoni K, Silky C, Rehak C, Yurko R, Look G, Rishton G, Safferstein H, Cruchaga C, Goate A, Cahill MA, Arancio O, Mach RH, Craven R, Head E, LeVine H 3rd, Spires-Jones TL, Catalano SM. Alzheimer's therapeutics targeting amyloid beta 1-42 oligomers II: Sigma-2/PGRMC1 receptors mediate Abeta 42 oligomer binding and synaptotoxicity. PLoS One. 2014;9(11):e111899. Epub 2014 Nov 12 PubMed.
Lambert MP, Barlow AK, Chromy BA, Edwards C, Freed R, Liosatos M, Morgan TE, Rozovsky I, Trommer B, Viola KL, Wals P, Zhang C, Finch CE, Krafft GA, Klein WL. Diffusible, nonfibrillar ligands derived from Abeta1-42 are potent central nervous system neurotoxins. Proc Natl Acad Sci U S A. 1998 May 26;95(11):6448-53. PubMed.
Reed MN, Hofmeister JJ, Jungbauer L, Welzel AT, Yu C, Sherman MA, Lesné S, LaDu MJ, Walsh DM, Ashe KH, Cleary JP. Cognitive effects of cell-derived and synthetically derived Aβ oligomers. Neurobiol Aging. 2011 Oct;32(10):1784-94. PubMed.
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