P60TRP interferes with the GPCR/secretase pathway to mediate neuronal survival and synaptogenesis.
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).
Affiliation: Department of Molecular and Cell Biology, School of Biological Sciences, College of Science, Nanyang Technological University, Singapore.Show MeSH
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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  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 , 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].
Affiliation: Department of Molecular and Cell Biology, School of Biological Sciences, College of Science, Nanyang Technological University, Singapore.