title: P60TRP interferes with the GPCR/secretase pathway to mediate neuronal survival and synaptogenesis.
abstract: In the present study, we show that overexpression of the G-protein-coupled receptor (GPCR)-associated sorting protein p60TRP (transcription regulator protein) in neural stem cells (NSCs) and in a transgenic mouse model modulates the phosphorylation and proteolytic processing of amyloid precursor protein (App), N-cadherin (Cdh2), presenilin (Psen) and τ protein (Mapt). Our results suggest that p60TRP is an inhibitor of Bace1 (β-site App cleaving enzyme) and Psen. We performed several apoptosis assays [Annexin-V, TdT-mediated dUTP Nick-End Labeling (TUNEL), caspase-3/7] using NSCs and PC12 cells (overexpressing p60TRP and knockdown of p60TRP) to substantiate the neuroprotective role of p60TRP. Functional analyses, both in vitro and in vivo, revealed that p60TRP promotes neurosynaptogenesis. Characterization of the cognitive function of p60TRP transgenic mice using the radial arm water maze test demonstrated that p60TRP improved memory and learning abilities. 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).
authors.affiliation: Department of Molecular and Cell Biology, School of Biological Sciences, College of Science, Nanyang Technological University, Singapore.
authors.forename: Manisha
authors.initials: M
authors.lastname: Mishra
authors.forename: Klaus
authors.initials: K
authors.lastname: Heese
mesh_terms: D000544:Alzheimer Disease / Q000378:metabolism / Q000503:physiopathology; D053829:Amyloid Precursor Protein Secretases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D016564:Amyloid beta-Protein Precursor / Q000378:metabolism; D000818:Animals; D017209:Apoptosis; D016282:Aspartic Acid Endopeptidases / Q000037:antagonists & inhibitors; D051792:Basic Helix-Loop-Helix Proteins / Q000235:genetics / Q000378:metabolism*; D001921:Brain / Q000166:cytology* / Q000378:metabolism / Q000503:physiopathology; D015820:Cadherins / Q000378:metabolism; D002454:Cell Differentiation; D002460:Cell Line; D057809:HEK293 Cells; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D008869:Microtubule-Associated Proteins / Q000096:biosynthesis; D058953:Neural Stem Cells / Q000502:physiology; D055495:Neurogenesis; D009474:Neurons / Q000378:metabolism / Q000502:physiology*; D016716:PC12 Cells; D053763:Presenilins / Q000378:metabolism; D034622:RNA Interference; D051381:Rats; D043562:Receptors, G-Protein-Coupled / Q000378:metabolism*; D011963:Receptors, GABA-A / Q000378:metabolism; D013569:Synapses / Q000502:physiology*; D016708:Synaptophysin / Q000096:biosynthesis; D050598:Vesicular Glutamate Transport Protein 1 / Q000096:biosynthesis; D016875:tau Proteins / Q000378:metabolism
chemical_list: D053829:Amyloid Precursor Protein Secretases; D016564:Amyloid beta-Protein Precursor; D016282:Aspartic Acid Endopeptidases; D051792:Basic Helix-Loop-Helix Proteins; D015820:Cadherins; D008869:Microtubule-Associated Proteins; D053763:Presenilins; D043562:Receptors, G-Protein-Coupled; D011963:Receptors, GABA-A; D016708:Synaptophysin; D050598:Vesicular Glutamate Transport Protein 1; D016875:tau Proteins; C497013:Bhlhb9 protein, rat; C489083:Cdh2 protein, mouse; C493465:Slc17a7 protein, mouse; C509282:Bace1 protein, mouse