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ABSTRACT: The amyloid precursor protein (APP) plays a crucial role in the pathogenesis of Alzheimer's disease. Here, we studied whether the lack of APP affects the synaptic properties in the dentate gyrus by measuring granule cell field potentials evoked by perforant path stimulation in anesthetized 9-11-month-old APP-deficient mice in vivo. We found decreased paired-pulse facilitation, indicating altered presynaptic short-term plasticity in the APP-deficient dentate gyrus. In contrast, excitatory synaptic strength and granule cell firing were unchanged in APP knockout mice. Likewise, long-term potentiation (LTP) induced by a theta-burst stimulation protocol was not impaired in the absence of APP. These findings suggest that the deletion of APP may affect presynaptic plasticity of synaptic transmission at the perforant path-granule cell synapse but leaves synaptic efficacy intact and LTP preserved, possibly due to functional redundancy within the APP gene family.
Experimental Brain Research 11/2011; 217(3-4):441-7. · 2.39 Impact Factor
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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
The EMBO Journal 06/2011; 30(11):2306. · 9.20 Impact Factor
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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
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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.
The EMBO Journal 06/2011; 30(11):2266-80. · 9.20 Impact Factor
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ABSTRACT: Proteolytical cleavage of the beta-amyloid precursor protein (APP) generates beta-amyloid, which is deposited in the brains of patients suffering from Alzheimer's disease (AD). Despite the well-established key role of APP for AD pathogenesis, the physiological function of APP and its close homologues APLP1 and APLP2 remains poorly understood. Previously, we generated APP(-/-) mice that proved viable, whereas APP(-/-)APLP2(-/-) mice and triple knockouts died shortly after birth, likely due to deficits of neuromuscular synaptic transmission. Here, we generated conditional knockout alleles for both APP and APLP2 in which the promoter and exon1 were flanked by loxP sites. No differences in expression were detectable between wt and floxed alleles, whereas null alleles were obtained upon crossing with Cre-transgenic deleter mice. These mice will now allow for tissue and time-point controlled knockout of both genes.
genesis 02/2010; 48(3):200-6. · 2.53 Impact Factor
