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 Live cell imaging of single neurotrophin receptor molecules on human neuron in Alzheimer’s disease

2020 ◽  
Author(s):  
Klaudia Barabás ◽  
Julianna Kobolák ◽  
Soma Godó ◽  
Dávid Ernszt ◽  
Miklós Kecskés ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Single Molecule ◽  
Critical Role ◽  
Live Cell ◽  
Neurotrophin Receptor ◽  
Neurotrophin Receptors ◽  
Healthy Individuals ◽  
Surface Movement ◽  
Receptor Dynamics

AbstractThe changes in the receptor dynamics such as the surface movement of the receptor molecules on the plasma membrane are essential to receptor function. However, whether the receptor dynamics are affected by disease conditions is unknown. Neurotrophin receptors such as TrkA and p75NTR play a critical role in neuronal survival and their functions are highly affected in Alzheimer’s disease (AD). Using live-cell single-molecule imaging of neurotrophin receptors we examined the surface trafficking of TrKA and p75NTR molecules on human induced pluripotent stem cells (hiPSCs) derived live neurons from presenilin 1 (PSEN1) mutant AD patients and healthy subjects. Here we report that surface trafficking of p75NTR molecules on neurites is faster than that of TrkA molecules in healthy controls. The surface dynamics of TrkA molecules were elevated in AD patients compared to healthy individuals. In contrast, the surface movement of p75NTR was significantly smaller in AD patients compared to healthy individuals. Interestingly, amyloid beta1-42 (Aβ1-42) administration increased the surface trafficking of both TrkA and p75NTR in healthy hiPSCs neurons. These findings provides the first evidence that the surface diffusion of TrkA and p75NTR molecules are altered in patients suffering from AD. Our data also suggest that Aβ1-42 may responsible for the alteration of the surface movements of TrkA but not for p75NTR.One Sentence SummaryThe surface movements of neurotrophin receptors such as TrkA and p75NTR are altered in neurons derived from patients suffering from familial Alzheimer’s disease.

scholarly journals Cerebellar Calcium-Binding Protein and Neurotrophin Receptor Defects in Down Syndrome and Alzheimer's Disease

2021 ◽  
Vol 13 ◽  
Author(s):  
Jennifer C. Miguel ◽  
Sylvia E. Perez ◽  
Michael Malek-Ahmadi ◽  
Elliott J. Mufson
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Down Syndrome ◽  
Calcium Binding ◽  
Critical Role ◽  
Neurotrophin Receptor ◽  
Strong Negative Correlation ◽  
Brush Cells ◽  
Plaque Load ◽  
Calbindin D

Cerebellar hypoplasia is a major characteristic of the Down syndrome (DS) brain. However, the consequences of trisomy upon cerebellar Purkinje cells (PC) and interneurons in DS are unclear. The present study performed a quantitative and qualitative analysis of cerebellar neurons immunostained with antibodies against calbindin D-28k (Calb), parvalbumin (Parv), and calretinin (Calr), phosphorylated and non-phosphorylated intermediate neurofilaments (SMI-34 and SMI-32), and high (TrkA) and low (p75NTR) affinity nerve growth factor (NGF) receptors as well as tau and amyloid in DS (n = 12), Alzheimer's disease (AD) (n = 10), and healthy non-dementia control (HC) (n = 8) cases. Our findings revealed higher Aβ42 plaque load in DS compared to AD and HC but no differences in APP/Aβ plaque load between HC, AD, and DS. The cerebellar cortex neither displayed Aβ40 containing plaques nor pathologic phosphorylated tau in any of the cases examined. The number and optical density (OD) measurements of Calb immunoreactive (-ir) PC soma and dendrites were similar between groups, while the number of PCs positive for Parv and SMI-32 were significantly reduced in AD and DS compared to HC. By contrast, the number of SMI-34-ir PC dystrophic axonal swellings, termed torpedoes, was significantly greater in AD compared to DS. No differences in SMI-32- and Parv-ir PC OD measurements were observed between groups. Conversely, total number of Parv- (stellate/basket) and Calr (Lugaro, brush, and Golgi)-positive interneurons were significantly reduced in DS compared to AD and HC. A strong negative correlation was found between counts for Parv-ir interneurons, Calr-ir Golgi and brush cells, and Aβ42 plaque load. Number of TrkA and p75NTR positive PCs were reduced in AD compared to HC. These findings suggest that disturbances in calcium binding proteins play a critical role in cerebellar neuronal dysfunction in adults with DS.

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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