The Secreted -Amyloid Precursor Protein Ectodomain APPs Is Sufficient to Rescue the Anatomical, Behavioral, and Electrophysiological Abnormalities of APP-Deficient Mice

Institute of Pharmacy and Molecular Biotechnology (IPMB), Universität Heidelberg, Heidelburg, Baden-Württemberg, Germany
The Journal of Neuroscience : The Official Journal of the Society for Neuroscience (Impact Factor: 6.34). 08/2007; 27(29):7817-26. DOI: 10.1523/JNEUROSCI.1026-07.2007
Source: PubMed


It is well established that the proteolytic processing of the beta-amyloid precursor protein (APP) generates beta-amyloid (Abeta), which plays a central role in the pathogenesis of Alzheimer's disease (AD). In contrast, the physiological role of APP and of its numerous proteolytic fragments and the question of whether a loss of these functions contributes to AD are still unknown. To address this question, we replaced the endogenous APP locus by gene-targeted alleles and generated two lines of knock-in mice that exclusively express APP deletion variants corresponding either to the secreted APP ectodomain (APPs alpha) or to a C-terminal (CT) truncation lacking the YENPTY interaction motif (APPdeltaCT15). Interestingly, the deltaCT15 deletion resulted in reduced turnover of holoAPP, increased cell surface expression, and strongly reduced Abeta levels in brain, likely because of reduced processing in the endocytic pathway. Most importantly, we demonstrate that in both APP knock-in lines the expression of APP N-terminal domains either grossly attenuated or completely rescued the prominent deficits of APP knock-out mice, such as reductions in brain and body weight, grip strength deficits, alterations in circadian locomotor activity, exploratory activity, and the impairment in spatial learning and long-term potentiation. Together, our data suggest that the APP C terminus is dispensable and that APPs alpha is sufficient to mediate the physiological functions of APP assessed by these tests.

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    • "The E1 domain was identified as the major interaction interface for homo-and heterodimerization of APP, APLP1 and APLP2 (Soba et al., 2005; Kaden et al., 2009; Dahms et al., 2010) suggesting a function of APP in cell adhesion (Herms et al., 2004; Young-Pearse et al., 2007). Aged mice of APP single knockouts show impairment in spatial learning (Müller et al., 1994; Phinney et al., 1999; Ring et al., 2007) and long-term potentiation (Seabrook et al., 1999; Ring et al., 2007; Tyan et al., 2012). Furthermore, a reduced number of dendritic spines (Lee et al., 2010; Tyan et al., 2012; Weyer et al., 2014) and a reduced overall dendritic length in the CA1 region has been reported (Seabrook et al., 1999). "
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    ABSTRACT: The Amyloid precursor protein (APP) plays a central role in Alzheimer’s disease (AD) and has essential synapse promoting functions. Synaptogenic activity as well as cell adhesion properties of APP presumably depend on trans-cellular dimerization via its extracellular domain. Since neuronal APP is extensively processed by secretases, it raises the question if APP shedding affects its cell adhesion and synaptogenic properties. We show that inhibition of APP shedding using cleavage deficient forms of APP or a dominant negative α-secretase strongly enhanced its cell adhesion and synaptogenic activity suggesting that synapse promoting function of APP is tightly regulated by α-secretase mediated processing, similar to other trans-cellular synaptic adhesion molecules.
    Full-text · Article · Nov 2014 · Frontiers in Cellular Neuroscience
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    • "Cultures were biolistically transfected with membrane-targeted farnesylated EGFP (fEGFP) which resulted in a small random population of fEGFP expressing neurons that were imaged and digitally reconstructed at day in vitro 17 (DIV17). We focused on CA1 as this region is highly vulnerable in AD, is one of the best studied brain regions with regard to synaptic plasticity, and we had previously demonstrated LTP defects at CA3/CA1 synapses in APP/APLP mutant mice [15,35]. To this end, we first studied APLP2-KO cultures as compared to wild type (WT) cultures. "
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    ABSTRACT: Synaptic dysfunction and synapse loss are key features of Alzheimer's pathogenesis. Previously, we showed an essential function of APP and APLP2 for synaptic plasticity, learning and memory. Here, we used organotypic hippocampal cultures to investigate the specific role(s) of APP family members and their fragments for dendritic complexity and spine formation of principal neurons within the hippocampus. Whereas CA1 neurons from APLP1-KO or APLP2-KO mice showed normal neuronal morphology and spine density, APP-KO mice revealed a highly reduced dendritic complexity in mid-apical dendrites. Despite unaltered morphology of APLP2-KO neurons, combined APP/APLP2-DKO mutants showed an additional branching defect in proximal apical dendrites, indicating redundancy and a combined function of APP and APLP2 for dendritic architecture. Remarkably, APP-KO neurons showed a pronounced decrease in spine density and reductions in the number of mushroom spines. No further decrease in spine density, however, was detectable in APP/APLP2-DKO mice. Mechanistically, using APPsalpha-KI mice lacking transmembrane APP and expressing solely the secreted APPsalpha fragment we demonstrate that APPsalpha expression alone is sufficient to prevent the defects in spine density observed in APP-KO mice. Collectively, these studies reveal a combined role of APP and APLP2 for dendritic architecture and a unique function of secreted APPs for spine density.
    Full-text · Article · Mar 2014
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    • "In contrast, the non-amyloidogenic pathway results in the production of soluble amyloid precursor protein-α (APPsα) and requires cleavage of APP via α- and γ-secretases. This pathway is believed to play a role in neuronal plasticity [5], [6], neuroprotection [7]–[11] and brain trauma [12]–[15]. "
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    ABSTRACT: The disintegrin and metalloproteinases ADAM10 and ADAM17 are regarded as the most important α-secretases involved in the physiological processing of amyloid precursor protein (APP) in brain. Since it has been suggested that processing of APP by α-secretases could be involved in the reorganization of the brain following injury, we studied mRNA expression of the two α-secretases Adam10 and Adam17, the ß-secretase Bace1, and the App-gene family (App, Aplp1, Aplp2) in the dentate gyrus of the mouse following entorhinal denervation. Using laser microdissection, tissue was harvested from the outer molecular layer and the granule cell layer of the denervated dentate gyrus. Expression levels of candidate genes were assessed using Affymetrix GeneChip Mouse Gene 1.0 ST arrays and reverse transcription-quantitative PCR, revealing an upregulation of Adam10 mRNA and Adam17 mRNA in the denervated outer molecular layer and an upregulation of Adam10 mRNA and App mRNA in the dentate granule cell layer. Immunolabeling for ADAM10 or ADAM17 in combination with markers for astro- and microglia revealed an increased labeling of ADAM10 and ADAM17 in the denervated outer molecular layer that was associated with reactive astrocytes but not with microglia. Collectively, these data show that denervation affects the expression level of APP and its two most important α-secretases. This suggests that APP-processing could be shifted towards the non-amyloidogenic pathway in denervated areas of the brain and, thus, towards the formation of neuroprotective APP cleavage products, such as APPsα.
    Full-text · Article · Jan 2014 · PLoS ONE
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