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.

scholarly journals Role of Tyrosine Phosphorylation in The Antioxidant Effects of The P75 Neurotrophin Receptor

2009 ◽  
Vol 2 (4) ◽  
pp. 238-246 ◽  
Author(s):  
Tong Zhang ◽  
Zhiping Mi ◽  
Nina F. Schor
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Oxidant Stress ◽  
Cholinergic Neurons ◽  
Adult Brain ◽  
Nucleus Basalis ◽  
Nucleus Basalis Of Meynert ◽  
Differential Sensitivity ◽  
Neurotrophin Receptor ◽  
P75 Neurotrophin Receptor

The p75 neurotrophin receptor (p75NTR) is an α-and γ-secretase substrate expressed preferentially in the cholinergic neurons of the nucleus basalis of Meynert, the hippocampus, and the cerebellum of the adult brain. Mutations of the γ-secretase, presenilin, have been implicated in familial Alzheimer's disease. Furthermore, oxidative and inflammatory injury to the cholinergic neurons of the nucleus basalis of Meynert and hippocampus plays a critical role in the pathology of Alzheimer's disease. The intracellular domain of p75NTR (p75ICD) is the α- and γ-secretase cleavage fragment of the holoreceptor that functions as an antioxidant in PC12 rat pheochromocytoma cells. Phosphorylation of the receptor is thought to be necessary for many of its functions, and two tyrosines in p75ICD have been among the functionally important phosphorylation sites. Site-directed mutagenesis was used to generate three p75ICD mutants that cannot be phosphorylated at either or both tyrosines, respectively. Each of these mutants was expressed in p75NTR-deficient PC12 cells to determine the effects of blocking phosphorylation at specific sites on the antioxidant activity of p75ICD. Interfering with phosphorylation at tyrosine-337 impairs antioxidant function, while interfering with phosphorylation at tyrosine-366 does not, and may in fact impart protection from oxidant stress. Neither MAPK (i.e., p38, ERK1, ERK2) content nor NF-κB activation accounts for the differential sensitivity to oxidant stress among the differentially phosphorylated p75NTR cell lines. However, differences in the time course of ERK1,2 phosphorylation among the lines account in large measure for their differential oxidant sensitivity. The phosphorylation state of specific sites on p75ICD may modulate the resistance of neurons in Alzheimer's disease-relevant brain regions to oxidant stress.

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 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 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 Stem cell derived basal forebrain cholinergic neurons from Alzheimer’s disease patients are more susceptible to cell death

2014 ◽  
Vol 9 (1) ◽  
pp. 3 ◽  
Author(s):  
Lishu Duan ◽  
Bula J Bhattacharyya ◽  
Abdelhak Belmadani ◽  
Liuliu Pan ◽  
Richard J Miller ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Cell Death ◽  
Stem Cell ◽  
Basal Forebrain ◽  
Cholinergic Neurons ◽  
Basal Forebrain Cholinergic Neurons

scholarly journals A novel P75‐neurotrophin receptor antagonist, EVT901, reduces neuroinflammation in the TGFAD344 rat model of Alzheimer’s disease

2020 ◽  
Vol 16 (S9) ◽  
Author(s):  
Min Su Kang ◽  
Thomas A Singleton ◽  
Arturo Aliaga Aliaga ◽  
Gassan Massarweh ◽  
Serge Gauthier ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Receptor Antagonist ◽  
Rat Model ◽  
Neurotrophin Receptor ◽  
P75 Neurotrophin Receptor ◽  
Model Of Alzheimer’S Disease
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