APP and APLP2 are essential at PNS and CNS synapses for transmission, spatial learning and LTP

• DOI: 10.1038/emboj.2011.164
• Publication Date: 2011-05-17T14:03:20Z
• Authors: Sascha W Weyer; Maja Klevanski; Andrea Delekate; Vootele Voikar; Dorothee Aydin; Meike Hick; Mikhail Filippov; Natalia Drost; Kristin L Schaller; Martina Saar; Miriam A Vogt; Peter Gass; Ayan Samanta; Andres Jäschke; Martin Korte; David P Wolfer; John H Caldwell; Ulrike C Müller
• Keywords: 10017 Institute of Anatomy; Neuromuscular Junction; 610 Medicine & health; Genetics and Molecular Biology; Biochemistry; Synaptic Transmission; Amyloid beta-Protein Precursor; Mice; 1300 General Biochemistry, Genetics and Molecular Biology; 11554 Zurich Center for Integrative Human Physiology (ZIHP); 2400 General Immunology and Microbiology; 1312 Molecular Biology; Animals; Learning; Biokemi; Molecular Biology; Crosses, Genetic; Alzheimer; amyloid precursor protein; knockout; learning; synaptic plasticity; Mice, Knockout; Molekylärbiologi; Neuronal Plasticity; General Immunology and Microbiology; General Neuroscience; Biochemistry and Molecular Biology; 2800 General Neuroscience; General Biochemistry; 570 Life sciences; biology; Biokemi och molekylärbiologi

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 APPsα knock-in (KI) mice expressing solely the secreted ectodomain APPsα. Here, we generated double mutants (APPsα-DM) by crossing APPsα-KI mice onto an APLP2-deficient background and show that APPsα rescues the postnatal lethality of the majority of APP/APLP2 double knockout mice. Surviving APPsα-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, APPsα-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 APPsα-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.