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

SUBMITTER: Weyer SW 

PROVIDER: S-EPMC3117640 | biostudies-literature | 2011 Jun

REPOSITORIES: biostudies-literature