scholarly journals Binding of beta-amyloid to the p75 neurotrophin receptor induces apoptosis. A possible mechanism for Alzheimer's disease.

1997 ◽  
Vol 100 (9) ◽  
pp. 2333-2340 ◽  
Author(s):  
M Yaar ◽  
S Zhai ◽  
P F Pilch ◽  
S M Doyle ◽  
P B Eisenhauer ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Beta Amyloid ◽  
Neurotrophin Receptor ◽  
P75 Neurotrophin Receptor

scholarly journals Live-Cell Imaging of Single Neurotrophin Receptor Molecules on Human Neurons in Alzheimer’s Disease

2021 ◽  
Vol 22 (24) ◽  
pp. 13260
Author(s):  
Klaudia Barabás ◽  
Julianna Kobolák ◽  
Soma Godó ◽  
Tamás Kovács ◽  
Dávid Ernszt ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Single Molecule ◽  
Critical Role ◽  
Live Cell ◽  
Neurotrophin Receptor ◽  
P75 Neurotrophin Receptor ◽  
Surface Movement ◽  
Human Neurons ◽  
Receptor Dynamics

Neurotrophin receptors such as the tropomyosin receptor kinase A receptor (TrkA) and the low-affinity binding p75 neurotrophin receptor p75NTR play a critical role in neuronal survival and their functions are altered in Alzheimer’s disease (AD). Changes in the dynamics of receptors on the plasma membrane are essential to receptor function. However, whether receptor dynamics are affected in different pathophysiological conditions is unexplored. Using live-cell single-molecule imaging, we examined the surface trafficking of TrkA and p75NTR molecules on live neurons that were derived from human-induced pluripotent stem cells (hiPSCs) of presenilin 1 (PSEN1) mutant familial AD (fAD) patients and non-demented control subjects. Our results show that the surface movement of TrkA and p75NTR and the activation of TrkA- and p75NTR-related phosphoinositide-3-kinase (PI3K)/serine/threonine-protein kinase (AKT) signaling pathways are altered in neurons that are derived from patients suffering from fAD compared to controls. These results provide evidence for altered surface movement of receptors in AD and highlight the importance of investigating receptor dynamics in disease conditions. Uncovering these mechanisms might enable novel therapies for AD.

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

2014 ◽  
Vol 2014 ◽  
pp. 1-6 ◽  
Author(s):  
Shine Devarajan ◽  
Jeya Sundara Sharmila
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Conformational Changes ◽  
Molecular Interactions ◽  
Neurodegenerative Disorder ◽  
Contact Point ◽  
Beta Amyloid ◽  
Dynamics Simulation ◽  
Neurotrophin Receptor ◽  
Receptor Binding Site

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 was not studied in detail. In view of this, we conducted a molecular docking and simulation study to investigate the binding behaviour of Aβ42 monomer with p75NTR ectodomain. Furthermore, we proposed a p75NTR-ectodomain-Aβ42 complex model. Our data revealed that, Aβ42 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 Aβ42 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.

scholarly journals Reduction of p75 neurotrophin receptor ameliorates the cognitive deficits in a model of Alzheimer's disease

2015 ◽  
Vol 36 (2) ◽  
pp. 740-752 ◽  
Author(s):  
Mark Murphy ◽  
Yvette M. Wilson ◽  
Ernesto Vargas ◽  
Kathryn M. Munro ◽  
Belinda Smith ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Cognitive Deficits ◽  
Neurotrophin Receptor ◽  
P75 Neurotrophin Receptor ◽  
Model Of Alzheimer’S Disease

scholarly journals TrkA-mediated endocytosis of p75-CTF prevents cholinergic neuron death upon γ-secretase inhibition

2021 ◽  
Vol 4 (4) ◽  
pp. e202000844
Author(s):  
María Luisa Franco ◽  
Irmina García-Carpio ◽  
Raquel Comaposada-Baró ◽  
Juan J Escribano-Saiz ◽  
Lucía Chávez-Gutiérrez ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Cell Death ◽  
Side Effects ◽  
Cholinergic Neurons ◽  
Neurotrophin Receptor ◽  
P75 Neurotrophin Receptor ◽  
Recognition Sequence ◽  
Neuron Death ◽  
Aged Patients

γ-secretase inhibitors (GSI) were developed to reduce the generation of Aβ peptide to find new Alzheimer’s disease treatments. Clinical trials on Alzheimer’s disease patients, however, showed several side effects that worsened the cognitive symptoms of the treated patients. The observed side effects were partially attributed to Notch signaling. However, the effect on other γ-secretase substrates, such as the p75 neurotrophin receptor (p75NTR) has not been studied in detail. p75NTR is highly expressed in the basal forebrain cholinergic neurons (BFCNs) during all life. Here, we show that GSI treatment induces the oligomerization of p75CTF leading to the cell death of BFCNs, and that this event is dependent on TrkA activity. The oligomerization of p75CTF requires an intact cholesterol recognition sequence (CRAC) and the constitutive binding of TRAF6, which activates the JNK and p38 pathways. Remarkably, TrkA rescues from cell death by a mechanism involving the endocytosis of p75CTF. These results suggest that the inhibition of γ-secretase activity in aged patients, where the expression of TrkA in the BFCNs is already reduced, could accelerate cholinergic dysfunction and promote neurodegeneration.

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