| First Author | Weyer SW | Year | 2011 |
| Journal | EMBO J | Volume | 30 |
| Issue | 11 | Pages | 2266-80 |
| PubMed ID | 21522131 | Mgi Jnum | J:173191 |
| Mgi Id | MGI:5013523 | Doi | 10.1038/emboj.2011.119 |
| Citation | Weyer SW, et al. (2011) APP and APLP2 are essential at PNS and CNS synapses for transmission, spatial learning and LTP. EMBO J 30(11):2266-80 |
| abstractText | Despite its key role in Alzheimer pathogenesis, the physiological function(s) of the amyloid precursor protein (APP) and its proteolytic fragments are still poorly understood. Previously, we generated APPsalpha knock-in (KI) mice expressing solely the secreted ectodomain APPsalpha. Here, we generated double mutants (APPsalpha-DM) by crossing APPsalpha-KI mice onto an APLP2-deficient background and show that APPsalpha rescues the postnatal lethality of the majority of APP/APLP2 double knockout mice. Surviving APPsalpha-DM mice exhibited impaired neuromuscular transmission, with reductions in quantal content, readily releasable pool, and ability to sustain vesicle release that resulted in muscular weakness. We show that these defects may be due to loss of an APP/Mint2/Munc18 complex. Moreover, APPsalpha-DM muscle showed fragmented post-synaptic specializations, suggesting impaired postnatal synaptic maturation and/or maintenance. Despite normal CNS morphology and unaltered basal synaptic transmission, young APPsalpha-DM mice already showed pronounced hippocampal dysfunction, impaired spatial learning and a deficit in LTP that could be rescued by GABA(A) receptor inhibition. Collectively, our data show that APLP2 and APP are synergistically required to mediate neuromuscular transmission, spatial learning and synaptic plasticity. |
