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P60TRP interferes with the GPCR/secretase pathway to mediate neuronal survival and synaptogenesis.

Mishra M, Heese K - J. Cell. Mol. Med. (2011)

Bottom Line: Our results suggest that p60TRP is an inhibitor of Bace1 (β-site App cleaving enzyme) and Psen.The improved cognitive functions could be attributed to increased synaptic connections and plasticity, which was confirmed by the modulation of the γ-aminobutyric acid receptor system and the elevated expression of microtubule-associated protein 2, synaptophysin and Slc17a7 (vesicle glutamate transporter, Vglut1), as well as by the inhibition of Cdh2 cleavage.In conclusion, interference with the p60TRP/ GPCR/secretase signalling pathway might be a new therapeutic target for the treatment of Alzheimer's disease (AD).

View Article: PubMed Central - PubMed

Affiliation: Department of Molecular and Cell Biology, School of Biological Sciences, College of Science, Nanyang Technological University, Singapore.

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Related in: MedlinePlus

P60TRP signalling based on the results obtained from different systems including NSCs, PC12 cells and p60TRP transgenic mice. P60TRP mediates neurosynaptogenesis by inducing PP2A activity which results in the dephosphorylation of App and the inhibition of Cdh2 cleavage through the inhibition of Psen. P60TRP also inhibits Bace1 (β-secretase)-mediated processing of App and promotes Adam10-mediated App cleavage resulting in enhanced production of sAppα and hence modulates synaptogenesis. Inhibition of Psen leads to reduced AICD signalling and neurogenesis as well as enhanced Mtap2 expression.
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fig11: P60TRP signalling based on the results obtained from different systems including NSCs, PC12 cells and p60TRP transgenic mice. P60TRP mediates neurosynaptogenesis by inducing PP2A activity which results in the dephosphorylation of App and the inhibition of Cdh2 cleavage through the inhibition of Psen. P60TRP also inhibits Bace1 (β-secretase)-mediated processing of App and promotes Adam10-mediated App cleavage resulting in enhanced production of sAppα and hence modulates synaptogenesis. Inhibition of Psen leads to reduced AICD signalling and neurogenesis as well as enhanced Mtap2 expression.

Mentions: Conversely, App is a conserved and ubiquitous transmembrane glycoprotein that is strongly implicated in the pathogenesis of AD; however, the physiological functions of App are still being investigated intensely [17, 69, 70]. During differentiation, the phosphorylation of the cytoplasmic domain of App at threonine 668 (Thr668) is regulated by Jnk3 and appears to be crucial for intracellular domain (AICD)-mediated signalling [39, 41, 71]. Recent findings have shown that phospho-App-bound Fe65 acts as a downstream element in the App signalling pathway, which negatively regulates neurogenesis [17, 72]. Increased expression of p60TRP induces the dephosphorylation of App by activating PP2A, which inhibits Bace1 [51] activity and causes reduced AICD signalling in p60TRP-overexpressing cells. P60TRP may modulate receptor shedding via both substrate desensitization/sensitization and specificity: a shift of the secretase cleavage products from Notch1 and Lifr (reduced or no Adam10 and Psen activity) to Cdh2 and App (enhanced Adam10 activity via Erk1/2 but reduced Bace1- and Psen-mediated cleavage). All of these effects of p60TRP in NSCs would enhance neurogenesis probably mediated by the inhibition of AICD signalling and enhanced sAppα release (Fig. 11) [17, 56, 58, 72–78]. This shift is also a non-amyloidogenic pathway because the α-secretase-cleavage precludes the formation of the neurotoxic β-amyloid peptide Aβ. Here, we also show that p60TRP, which interacts with PP2A [16], induces enhanced cleavage of the phosphorylated Mapt protein and increases PP2A activity, consistent with previous reports demonstrating an association between PP2A and Jnk activity in tauopathy [29, 30, 37].


P60TRP interferes with the GPCR/secretase pathway to mediate neuronal survival and synaptogenesis.

Mishra M, Heese K - J. Cell. Mol. Med. (2011)

P60TRP signalling based on the results obtained from different systems including NSCs, PC12 cells and p60TRP transgenic mice. P60TRP mediates neurosynaptogenesis by inducing PP2A activity which results in the dephosphorylation of App and the inhibition of Cdh2 cleavage through the inhibition of Psen. P60TRP also inhibits Bace1 (β-secretase)-mediated processing of App and promotes Adam10-mediated App cleavage resulting in enhanced production of sAppα and hence modulates synaptogenesis. Inhibition of Psen leads to reduced AICD signalling and neurogenesis as well as enhanced Mtap2 expression.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC3822957&req=5

fig11: P60TRP signalling based on the results obtained from different systems including NSCs, PC12 cells and p60TRP transgenic mice. P60TRP mediates neurosynaptogenesis by inducing PP2A activity which results in the dephosphorylation of App and the inhibition of Cdh2 cleavage through the inhibition of Psen. P60TRP also inhibits Bace1 (β-secretase)-mediated processing of App and promotes Adam10-mediated App cleavage resulting in enhanced production of sAppα and hence modulates synaptogenesis. Inhibition of Psen leads to reduced AICD signalling and neurogenesis as well as enhanced Mtap2 expression.
Mentions: Conversely, App is a conserved and ubiquitous transmembrane glycoprotein that is strongly implicated in the pathogenesis of AD; however, the physiological functions of App are still being investigated intensely [17, 69, 70]. During differentiation, the phosphorylation of the cytoplasmic domain of App at threonine 668 (Thr668) is regulated by Jnk3 and appears to be crucial for intracellular domain (AICD)-mediated signalling [39, 41, 71]. Recent findings have shown that phospho-App-bound Fe65 acts as a downstream element in the App signalling pathway, which negatively regulates neurogenesis [17, 72]. Increased expression of p60TRP induces the dephosphorylation of App by activating PP2A, which inhibits Bace1 [51] activity and causes reduced AICD signalling in p60TRP-overexpressing cells. P60TRP may modulate receptor shedding via both substrate desensitization/sensitization and specificity: a shift of the secretase cleavage products from Notch1 and Lifr (reduced or no Adam10 and Psen activity) to Cdh2 and App (enhanced Adam10 activity via Erk1/2 but reduced Bace1- and Psen-mediated cleavage). All of these effects of p60TRP in NSCs would enhance neurogenesis probably mediated by the inhibition of AICD signalling and enhanced sAppα release (Fig. 11) [17, 56, 58, 72–78]. This shift is also a non-amyloidogenic pathway because the α-secretase-cleavage precludes the formation of the neurotoxic β-amyloid peptide Aβ. Here, we also show that p60TRP, which interacts with PP2A [16], induces enhanced cleavage of the phosphorylated Mapt protein and increases PP2A activity, consistent with previous reports demonstrating an association between PP2A and Jnk activity in tauopathy [29, 30, 37].

Bottom Line: Our results suggest that p60TRP is an inhibitor of Bace1 (β-site App cleaving enzyme) and Psen.The improved cognitive functions could be attributed to increased synaptic connections and plasticity, which was confirmed by the modulation of the γ-aminobutyric acid receptor system and the elevated expression of microtubule-associated protein 2, synaptophysin and Slc17a7 (vesicle glutamate transporter, Vglut1), as well as by the inhibition of Cdh2 cleavage.In conclusion, interference with the p60TRP/ GPCR/secretase signalling pathway might be a new therapeutic target for the treatment of Alzheimer's disease (AD).

View Article: PubMed Central - PubMed

Affiliation: Department of Molecular and Cell Biology, School of Biological Sciences, College of Science, Nanyang Technological University, Singapore.

Show MeSH
Related in: MedlinePlus