Alzheimer's therapeutics targeting Amyloid Beta 1'42 oligomers II: Sigma-2/PGRMC1 receptors mediate Abeta 42 Oligomer binding and synaptotoxicity

Nicholas J. Izzo, Jinbin Xu, Chenbo Zeng, Molly J. Kirk, Kelsie Mozzoni, Colleen Silky, Courtney Rehak, Raymond Yurko, Gary Look, Gilbert Rishton, Hank Safferstein, Carlos Cruchaga, Alison Goate, Michael Cahill, Ottavio Arancio, Robert H. Mach, Rolf Craven, Elizabeth Head, Harry Levine III, Tara L. Spires-JonesSusan M. Catalano

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Abstract

Amyloid beta (Abeta) 1-42 oligomers accumulate in brains of patients with Mild Cognitive Impairment (MCI) and disrupt synaptic plasticity processes that underlie memory formation. Synaptic binding of Abeta oligomers to several putative receptor proteins is reported to inhibit long-term potentiation, affect membrane trafficking and induce reversible spine loss in neurons, leading to impaired cognitive performance and ultimately to anterograde amnesia in the early stages of Alzheimer's disease (AD). We have identified a receptor not previously associated with AD that mediates the binding of Abeta oligomers to neurons, and describe novel therapeutic antagonists of this receptor capable of blocking Abeta toxic effects on synapses in vitro and cognitive deficits in vivo. Knockdown of sigma-2/PGRMC1 (progesterone receptor membrane component 1) protein expression in vitro using siRNA results in a highly correlated reduction in binding of exogenous Abeta oligomers to neurons of more than 90%. Expression of sigma-2/PGRMC1 is upregulated in vitro by treatment with Abeta oligomers, and is dysregulated in Alzheimer's disease patients' brain compared to age-matched, normal individuals. Specific, high affinity small molecule receptor antagonists and antibodies raised against specific regions on this receptor can displace synthetic Abeta oligomer binding to synaptic puncta in vitro and displace endogenous human AD patient oligomers from brain tissue sections in a dose-dependent manner. These receptor antagonists prevent and reverse the effects of Abeta oligomers on membrane trafficking and synapse loss in vitro and cognitive deficits in AD mouse models. These findings suggest sigma-2/PGRMC1 receptors mediate saturable oligomer binding to synaptic puncta on neurons and that brain penetrant, small molecules can displace endogenous and synthetic oligomers and improve cognitive deficits in AD models. We propose that sigma-2/PGRMC1 is a key mediator of the pathological effects of Abeta oligomers in AD and is a tractable target for small molecule disease-modifying therapeutics.
Original languageEnglish
Pages (from-to)1-15
Number of pages15
JournalPLoS One
Volume9
Issue number11
DOIs
Publication statusPublished - Nov 2014

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amyloid
Oligomers
Amyloid
Alzheimer disease
Alzheimer Disease
therapeutics
receptors
neurons
Neurons
Brain
brain
antagonists
Therapeutics
disease models
Synapses
synapse
Membranes
Anterograde Amnesia
Molecules
Neuronal Plasticity

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Izzo, Nicholas J. ; Xu, Jinbin ; Zeng, Chenbo ; Kirk, Molly J. ; Mozzoni, Kelsie ; Silky, Colleen ; Rehak, Courtney ; Yurko, Raymond ; Look, Gary ; Rishton, Gilbert ; Safferstein, Hank ; Cruchaga, Carlos ; Goate, Alison ; Cahill, Michael ; Arancio, Ottavio ; Mach, Robert H. ; Craven, Rolf ; Head, Elizabeth ; III, Harry Levine ; Spires-Jones, Tara L. ; Catalano, Susan M. / Alzheimer's therapeutics targeting Amyloid Beta 1'42 oligomers II : Sigma-2/PGRMC1 receptors mediate Abeta 42 Oligomer binding and synaptotoxicity. In: PLoS One. 2014 ; Vol. 9, No. 11. pp. 1-15.
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title = "Alzheimer's therapeutics targeting Amyloid Beta 1'42 oligomers II: Sigma-2/PGRMC1 receptors mediate Abeta 42 Oligomer binding and synaptotoxicity",
abstract = "Amyloid beta (Abeta) 1-42 oligomers accumulate in brains of patients with Mild Cognitive Impairment (MCI) and disrupt synaptic plasticity processes that underlie memory formation. Synaptic binding of Abeta oligomers to several putative receptor proteins is reported to inhibit long-term potentiation, affect membrane trafficking and induce reversible spine loss in neurons, leading to impaired cognitive performance and ultimately to anterograde amnesia in the early stages of Alzheimer's disease (AD). We have identified a receptor not previously associated with AD that mediates the binding of Abeta oligomers to neurons, and describe novel therapeutic antagonists of this receptor capable of blocking Abeta toxic effects on synapses in vitro and cognitive deficits in vivo. Knockdown of sigma-2/PGRMC1 (progesterone receptor membrane component 1) protein expression in vitro using siRNA results in a highly correlated reduction in binding of exogenous Abeta oligomers to neurons of more than 90{\%}. Expression of sigma-2/PGRMC1 is upregulated in vitro by treatment with Abeta oligomers, and is dysregulated in Alzheimer's disease patients' brain compared to age-matched, normal individuals. Specific, high affinity small molecule receptor antagonists and antibodies raised against specific regions on this receptor can displace synthetic Abeta oligomer binding to synaptic puncta in vitro and displace endogenous human AD patient oligomers from brain tissue sections in a dose-dependent manner. These receptor antagonists prevent and reverse the effects of Abeta oligomers on membrane trafficking and synapse loss in vitro and cognitive deficits in AD mouse models. These findings suggest sigma-2/PGRMC1 receptors mediate saturable oligomer binding to synaptic puncta on neurons and that brain penetrant, small molecules can displace endogenous and synthetic oligomers and improve cognitive deficits in AD models. We propose that sigma-2/PGRMC1 is a key mediator of the pathological effects of Abeta oligomers in AD and is a tractable target for small molecule disease-modifying therapeutics.",
keywords = "Oligomers, Neurons, Alzheimer's disease, Membrane Proteins, Small molecules, Membrane trafficking, Cell binding, Cognitive impairment",
author = "Izzo, {Nicholas J.} and Jinbin Xu and Chenbo Zeng and Kirk, {Molly J.} and Kelsie Mozzoni and Colleen Silky and Courtney Rehak and Raymond Yurko and Gary Look and Gilbert Rishton and Hank Safferstein and Carlos Cruchaga and Alison Goate and Michael Cahill and Ottavio Arancio and Mach, {Robert H.} and Rolf Craven and Elizabeth Head and III, {Harry Levine} and Spires-Jones, {Tara L.} and Catalano, {Susan M.}",
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year = "2014",
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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, M, Arancio, O, Mach, RH, Craven, R, Head, E, III, HL, Spires-Jones, TL & Catalano, SM 2014, 'Alzheimer's therapeutics targeting Amyloid Beta 1'42 oligomers II: Sigma-2/PGRMC1 receptors mediate Abeta 42 Oligomer binding and synaptotoxicity', PLoS One, vol. 9, no. 11, pp. 1-15. https://doi.org/10.1371/journal.pone.0111899

Alzheimer's therapeutics targeting Amyloid Beta 1'42 oligomers II : Sigma-2/PGRMC1 receptors mediate Abeta 42 Oligomer binding and synaptotoxicity. / Izzo, Nicholas J.; Xu, Jinbin; Zeng, Chenbo; Kirk, Molly J.; Mozzoni, Kelsie; Silky, Colleen; Rehak, Courtney; Yurko, Raymond; Look, Gary; Rishton, Gilbert; Safferstein, Hank; Cruchaga, Carlos; Goate, Alison; Cahill, Michael; Arancio, Ottavio; Mach, Robert H.; Craven, Rolf; Head, Elizabeth; III, Harry Levine; Spires-Jones, Tara L.; Catalano, Susan M.

In: PLoS One, Vol. 9, No. 11, 11.2014, p. 1-15.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Alzheimer's therapeutics targeting Amyloid Beta 1'42 oligomers II

T2 - Sigma-2/PGRMC1 receptors mediate Abeta 42 Oligomer binding and synaptotoxicity

AU - Izzo, Nicholas J.

AU - Xu, Jinbin

AU - Zeng, Chenbo

AU - Kirk, Molly J.

AU - Mozzoni, Kelsie

AU - Silky, Colleen

AU - Rehak, Courtney

AU - Yurko, Raymond

AU - Look, Gary

AU - Rishton, Gilbert

AU - Safferstein, Hank

AU - Cruchaga, Carlos

AU - Goate, Alison

AU - Cahill, Michael

AU - Arancio, Ottavio

AU - Mach, Robert H.

AU - Craven, Rolf

AU - Head, Elizabeth

AU - III, Harry Levine

AU - Spires-Jones, Tara L.

AU - Catalano, Susan M.

N1 - Includes bibliographical references.

PY - 2014/11

Y1 - 2014/11

N2 - Amyloid beta (Abeta) 1-42 oligomers accumulate in brains of patients with Mild Cognitive Impairment (MCI) and disrupt synaptic plasticity processes that underlie memory formation. Synaptic binding of Abeta oligomers to several putative receptor proteins is reported to inhibit long-term potentiation, affect membrane trafficking and induce reversible spine loss in neurons, leading to impaired cognitive performance and ultimately to anterograde amnesia in the early stages of Alzheimer's disease (AD). We have identified a receptor not previously associated with AD that mediates the binding of Abeta oligomers to neurons, and describe novel therapeutic antagonists of this receptor capable of blocking Abeta toxic effects on synapses in vitro and cognitive deficits in vivo. Knockdown of sigma-2/PGRMC1 (progesterone receptor membrane component 1) protein expression in vitro using siRNA results in a highly correlated reduction in binding of exogenous Abeta oligomers to neurons of more than 90%. Expression of sigma-2/PGRMC1 is upregulated in vitro by treatment with Abeta oligomers, and is dysregulated in Alzheimer's disease patients' brain compared to age-matched, normal individuals. Specific, high affinity small molecule receptor antagonists and antibodies raised against specific regions on this receptor can displace synthetic Abeta oligomer binding to synaptic puncta in vitro and displace endogenous human AD patient oligomers from brain tissue sections in a dose-dependent manner. These receptor antagonists prevent and reverse the effects of Abeta oligomers on membrane trafficking and synapse loss in vitro and cognitive deficits in AD mouse models. These findings suggest sigma-2/PGRMC1 receptors mediate saturable oligomer binding to synaptic puncta on neurons and that brain penetrant, small molecules can displace endogenous and synthetic oligomers and improve cognitive deficits in AD models. We propose that sigma-2/PGRMC1 is a key mediator of the pathological effects of Abeta oligomers in AD and is a tractable target for small molecule disease-modifying therapeutics.

AB - Amyloid beta (Abeta) 1-42 oligomers accumulate in brains of patients with Mild Cognitive Impairment (MCI) and disrupt synaptic plasticity processes that underlie memory formation. Synaptic binding of Abeta oligomers to several putative receptor proteins is reported to inhibit long-term potentiation, affect membrane trafficking and induce reversible spine loss in neurons, leading to impaired cognitive performance and ultimately to anterograde amnesia in the early stages of Alzheimer's disease (AD). We have identified a receptor not previously associated with AD that mediates the binding of Abeta oligomers to neurons, and describe novel therapeutic antagonists of this receptor capable of blocking Abeta toxic effects on synapses in vitro and cognitive deficits in vivo. Knockdown of sigma-2/PGRMC1 (progesterone receptor membrane component 1) protein expression in vitro using siRNA results in a highly correlated reduction in binding of exogenous Abeta oligomers to neurons of more than 90%. Expression of sigma-2/PGRMC1 is upregulated in vitro by treatment with Abeta oligomers, and is dysregulated in Alzheimer's disease patients' brain compared to age-matched, normal individuals. Specific, high affinity small molecule receptor antagonists and antibodies raised against specific regions on this receptor can displace synthetic Abeta oligomer binding to synaptic puncta in vitro and displace endogenous human AD patient oligomers from brain tissue sections in a dose-dependent manner. These receptor antagonists prevent and reverse the effects of Abeta oligomers on membrane trafficking and synapse loss in vitro and cognitive deficits in AD mouse models. These findings suggest sigma-2/PGRMC1 receptors mediate saturable oligomer binding to synaptic puncta on neurons and that brain penetrant, small molecules can displace endogenous and synthetic oligomers and improve cognitive deficits in AD models. We propose that sigma-2/PGRMC1 is a key mediator of the pathological effects of Abeta oligomers in AD and is a tractable target for small molecule disease-modifying therapeutics.

KW - Oligomers

KW - Neurons

KW - Alzheimer's disease

KW - Membrane Proteins

KW - Small molecules

KW - Membrane trafficking

KW - Cell binding

KW - Cognitive impairment

U2 - 10.1371/journal.pone.0111899

DO - 10.1371/journal.pone.0111899

M3 - Article

C2 - 25390692

VL - 9

SP - 1

EP - 15

JO - PLoS One

JF - PLoS One

SN - 1932-6203

IS - 11

ER -