title: APP and APLP2 are essential at PNS and CNS synapses for transmission, spatial learning and LTP.
abstract: 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.
authors.affiliation: Department of Bioinformatics and Functional Genomics, Institute of Pharmacy and Molecular Biotechnology, Heidelberg University, Heidelberg, Germany.
authors.forename: Sascha W
authors.initials: SW
authors.lastname: Weyer
authors.forename: Maja
authors.initials: M
authors.lastname: Klevanski
authors.forename: Andrea
authors.initials: A
authors.lastname: Delekate
authors.forename: Vootele
authors.initials: V
authors.lastname: Voikar
authors.forename: Dorothee
authors.initials: D
authors.lastname: Aydin
authors.forename: Meike
authors.initials: M
authors.lastname: Hick
authors.forename: Mikhail
authors.initials: M
authors.lastname: Filippov
authors.forename: Natalia
authors.initials: N
authors.lastname: Drost
authors.forename: Kristin L
authors.initials: KL
authors.lastname: Schaller
authors.forename: Martina
authors.initials: M
authors.lastname: Saar
authors.forename: Miriam A
authors.initials: MA
authors.lastname: Vogt
authors.forename: Peter
authors.initials: P
authors.lastname: Gass
authors.forename: Ayan
authors.initials: A
authors.lastname: Samanta
authors.forename: Andres
authors.initials: A
authors.lastname: Jäschke
authors.forename: Martin
authors.initials: M
authors.lastname: Korte
authors.forename: David P
authors.initials: DP
authors.lastname: Wolfer
authors.forename: John H
authors.initials: JH
authors.lastname: Caldwell
authors.forename: Ulrike C
authors.initials: UC
authors.lastname: Müller
mesh_terms: D016564:Amyloid beta-Protein Precursor / Q000172:deficiency / Q000235:genetics*; D000818:Animals; D003433:Crosses, Genetic; D007858:Learning; D051379:Mice; D018345:Mice, Knockout; D009469:Neuromuscular Junction / Q000502:physiology; D009473:Neuronal Plasticity; D009435:Synaptic Transmission
chemical_list: D016564:Amyloid beta-Protein Precursor; C492952:Aplp2 protein, mouse