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

作者：Weyer Sascha W; Klevanski Maja; Delekate Andrea; Voikar Vootele; Aydin Dorothee; Hick Meike; Filippov Mikhail; Drost Natalia; Schaller Kristin L; Saar Martina; Vogt Miriam A; Gass Peter; Samanta Ayan; Jaeschke Andres; Korte Martin; Wolfer David P; Caldwell John H; Mueller Ulrike C

来源：The EMBO Journal, 2011, 30(11): 2266-2280.

DOI：10.1038/emboj.2011.119

• Alzheimer
• amyloid precursor protein
• knockout
• learning
• synaptic plasticity

Despite its key role in Alzheimer pathogenesis, the physiological s) of the amyloid precursor protein (APP) and its proteolytic fragments are still poorly understood. Previously, we generated APPs alpha knock-in (KI) mice expressing solely the secreted ectodomain APPs alpha. Here, we generated double mutants (APPs alpha-DM) by crossing APPs alpha-KI mice onto an APLP2-deficient background and show that APPs alpha rescues the postnatal lethality of the majority of APP/APLP2 double knockout mice. Surviving APPs alpha-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, APPsa-DM muscle showed fragmented postsynaptic specializations, suggesting impaired postnatal synaptic maturation and/or maintenance. Despite normal CNS morphology and unaltered basal synaptic transmission, young APPsa-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. The EMBO Journal (2011) 30, 2266-2280. doi:10.1038/emboj.2011.119; Published online 26 April 2011

• 出版日期2011-6-1
• 单位上海市精神卫生中心