Presenilin-1/γ-Secretase Controls Glutamate Release, Tyrosine Phosphorylation, and Surface Expression of N-Methyl-d-aspartate Receptor (NMDAR) Subunit GluN2B

Abstract

Background: Presenilin-1/␥-secretase is critical to neuronal function. Results: Inhibition of presenilin-1/␥-secretase increases release of glutamate, stimulating NMDAR and calpain while decreasing phosphorylation and surface expression of neuronal GluN2B. Conclusion: Presenilin-1/␥-secretase regulates glutamate release, NMDAR-dependent calpain activity, and modification of GluN2B. Significance: This study reveals a role for ␥-secretase in release of glutamate, a neurotransmitter central to neuronal function, and excitotoxicity, a stress important to neurodegeneration.

Presenilin1/γ‐secretase protects neurons from glucose deprivation‐induced death by regulating miR‐212 and PEA15

“…Because CREB activity is regulated by NMDARs (42,52), we asked whether the PS1/g-secretase system might affect CREB activity via this receptor. This possibility is also supported by reports that the reduction of PS1 or the inhibition of g-secretase reduce cell surface expression of NMDAR (41,53) and that NMDAR currents are affected by PS1 Figure 6. PS1/g-secretase regulates CREB activation.…”

“…Recently, it was reported that the absence of PS1 or the inhibition of g-secretase activity activates the NMDA receptor (NMDAR) (41), and literature indicates that CREB activity is modulated by NMDAR (42). To further examine the effects of the NMDAR-CREB signaling cascade, we thus used MK801, an antagonist of NMDAR, to investigate whether blocking NMDAR changed CREB phosphorylation.…”

Presenilin 1 is necessary for neuronal, but not glial, EGFR expression and neuroprotectionviaγ-secretase-independent transcriptional mechanisms

“…All animal experiments were carried out according to regulations of Mount Sinai Medical Center. Primary cortical neuronal cultures (PCNC) were prepared from embryonic day (E) 15.5 mouse embryo brains, plated on poly‐ d ‐lysine‐coated plates in Neurobasal medium as reported elsewhere (3, 28, 29) and kept in vitro before use as indicated in figure legends. At 9 d in vitro (DIV), postmitotic neurons represented more than 95% of cultured cells (Supplemental Fig.…”

“…GRN) overnight. The next day, the medium was switched to HBSS containing Hb‐EGF, EGF, or PGRN for 30 min, followed by 50 μM glutamate incubation for 3 h, and cell viability was evaluated by MTT assay and normalized to nontreated cells, as previously described (3, 29). No significant effect compared to nontreated was observed when growth factors alone were added to cultures.…”

Μηχανισμοί κυτταρικού θανάτου των νευρώνων του εγκεφάλου στη νόσο του Alzheimer

“…were prepared from E 15.5 mouse embryo brains, plated on poly-D-lysine-coated plates in Neurobasal medium as reported (3,28,29) and kept in vitro before use as indicated in figure legends. At 9 days in vitro (DIV) postmitotic neurons represent more than 95% of cultured cells (3 and Supplementary Fig.…”