Dataset Information

Computational Studies of Beta Amyloid (A?42) with p75NTR Receptor: A Novel Therapeutic Target in Alzheimer's Disease.

ABSTRACT: Alzheimer's disease is a neurodegenerative disorder characterized by the accumulation of beta amyloid plaques (A?) which can induce neurite degeneration and progressive dementia. It has been identified that neuronal apoptosis is induced by binding of A?42 to pan neurotrophin receptor (p75NTR) and gave the possibility that beta amyloid oligomer is a ligand for p75NTR. However, the atomic contact point responsible for molecular interactions and conformational changes of the protein upon binding was not studied in detail. In view of this, we conducted a molecular docking and simulation study to investigate the binding behaviour of A?42 monomer with p75NTR ectodomain. Furthermore, we proposed a p75NTR-ectodomain-A?42 complex model. Our data revealed that, A?42 specifically recognizes CRD1 and CRD2 domains of the receptor and formed a "cap" like structure at the N-terminal of receptor which is stabilized by a network of hydrogen bonds. These findings are supported by molecular dynamics simulation that A?42 showed distinct structural alterations at N- and C-terminal regions due to the influence of the receptor binding site. Overall, the present study gives more structural insight on the molecular interactions of beta amyloid protein involved in the activation of p75NTR receptor.

SUBMITTER: Devarajan S

PROVIDER: S-EPMC4244936 | biostudies-literature | 2014

REPOSITORIES: biostudies-literature

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Publications

Computational Studies of Beta Amyloid (Aβ42) with p75NTR Receptor: A Novel Therapeutic Target in Alzheimer's Disease.

Devarajan Shine S Sharmila Jeya Sundara JS

Advances in bioinformatics 20141111

Alzheimer's disease is a neurodegenerative disorder characterized by the accumulation of beta amyloid plaques (Aβ) which can induce neurite degeneration and progressive dementia. It has been identified that neuronal apoptosis is induced by binding of Aβ42 to pan neurotrophin receptor (p75NTR) and gave the possibility that beta amyloid oligomer is a ligand for p75NTR. However, the atomic contact point responsible for molecular interactions and conformational changes of the protein upon binding wa ...[more]

PMID: 25477959

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Project description: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.

Dataset Information

Computational Studies of Beta Amyloid (A?42) with p75NTR Receptor: A Novel Therapeutic Target in Alzheimer's Disease.

Publications

Computational Studies of Beta Amyloid (Aβ42) with p75NTR Receptor: A Novel Therapeutic Target in Alzheimer's Disease.

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