Weyer, S W; Klevanski, M; Delekate, A; Voikar, V; Aydin, D; Hick, M; Filippov, M; Drost, N; Schaller, K L; Saar, M; Vogt, M A; Gass, P; Samanta, A; Jäschke, A; Korte, M; Wolfer, D P; Caldwell, J H; Müller, U C (2011). APP and APLP2 are essential at PNS and CNS synapses for transmission, spatial learning and LTP. The EMBO Journal, 30(11):2266-2280.
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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.
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|Item Type:||Journal Article, refereed, original work|
|Communities & Collections:||04 Faculty of Medicine > Institute of Anatomy
04 Faculty of Medicine > Center for Integrative Human Physiology
|DDC:||570 Life sciences; biology
610 Medicine & health
|Deposited On:||28 Jan 2012 19:08|
|Last Modified:||27 Nov 2013 22:10|
|Publisher:||Nature Publishing Group|
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