Alzheimer's disease (AD) is a chronic neurodegenerative disorder caused by a combination of events impairing normal neuronal function. Here we found a molecular bridge between key elements of primary and secondary pathogenic events in AD, namely the elements of the amyloid cascade and synaptic dysfunction associated with the glutamatergic system. In fact, we report that synapse-associated protein-97 (SAP97), a protein involved in dynamic trafficking of proteins to the excitatory synapse, is responsible for driving ADAM10 (a disintegrin and metalloproteinase 10, the most accredited candidate for alpha-secretase) to the postsynaptic membrane, by a direct interaction through its Src homology 3 domain. NMDA receptor activation mediates this event and positively modulates alpha-secretase activity. Furthermore, perturbing ADAM10/SAP97 association in vivo by cell-permeable peptides impairs ADAM10 localization in postsynaptic membranes and consequently decreases the physiological amyloid precursor protein (APP) metabolism. Our findings indicate that glutamatergic synapse activation through NMDA receptor promotes the non-amyloidogenic APP cleavage, strengthening the correlation between APP metabolism and synaptic plasticity.
"Together, this indicates a dual role of APP for spine structure: an early requirement of APP at stages of spine formation/maturation and also for the maintenance of spines during aging. Further support for a synaptotrophic role of APP and APPsα comes from transgenic mice with moderate overexpression of human WT APP , or indirect up-regulation of APPsα by transgenic expression of the α-secretase ADAM10 , that is enriched at synaptic contacts , which all lead to increased synaptic density. In Tg2576 mice expression of mutant huAPP increased spine density in CA1 and cortical neurons of young mice prior to plaque deposition possibly via APPsα, whereas spine density was decreased in aged animals, presumably due to Aβ-mediated synaptotoxic effects [16,17]. "
[Show abstract][Hide abstract] 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.
"Conversely, disrupting ADAM10-SAP97 interaction redistributes ADAM10 localization from postsynaptic membranes, thereby suppresses non-amyloidogenic APP processing. As a consequence, this results in Aβ accumulation, MAPT hyperphosphorylation, and impaired behavioral performance and synaptic dysfunction in mice, thereby recapitulating early-stage AD phenotypes . In the hippocampus of AD patients, the association of ADAM10 with SAP97 is found to be reduced , implying a dysfunction in SAP97-mediated ADAM10 sorting in AD. "
[Show abstract][Hide abstract] ABSTRACT: The beta-amyloid (Abeta) peptide has been postulated to be a key determinant in the pathogenesis of Alzheimer's disease (AD). Abeta is produced through sequential cleavage of the beta-amyloid precursor protein (APP) by beta- and gamma-secretases. APP and relevant secretases are transmembrane proteins and traffic through the secretory pathway in a highly regulated fashion. Perturbation of their intracellular trafficking may affect dynamic interactions among these proteins, thus altering Abeta generation and accelerating disease pathogenesis. Herein, we review recent progress elucidating the regulation of intracellular trafficking of these essential protein components in AD.
"For example, prolonged activation of NMDAR with sub-maximal doses of agonist ,  or specific stimulation of extrasynaptic NMDAR , promotes amyloidogenic processing of APP and hence increases Aβ production. In contrast, direct activation of synaptic NMDAR favours non-amyloidogenic α-secretase-mediated APP processing to reduce Aβ production and release , first recruiting ADAM-10, towards the cell surface  and then upregulating ADAM-10 expression in an ERK-dependent manner . Administration of NMDAR antagonists or channel blockers increases Aβ levels both in vitro and in vivo
,  and similar elevations in Aβ are observed following the administration of MEK/ERK inhibitors . "
[Show abstract][Hide abstract] ABSTRACT: Soluble oligomeric amyloid β peptide (Aβ) generated from processing of the amyloid precursor protein (APP) plays a central role in the pathogenesis of Alzheimer's Disease (AD) and through actions at glutamatergic synapses affects excitability and plasticity. The physiological control of APP processing is not fully understood but stimulation of synaptic NMDA receptors (NMDAR) can suppress Aβ levels through an ERK-dependent increase in α-secretase activity. AMPA-type glutamate receptors (AMPAR) couple to ERK phosphorylation independently of NMDAR activation raising the possibility that stimulation of AMPAR might similarly promote non-amyloidogenic APP processing. We have tested this hypothesis by investigating whether AMPAR directly regulate APP processing in cultured mouse cortical neurons, by analyzing APP C-terminal fragments (CTFs), soluble APP (sAPP), Aβ levels, and cleavage of an APP-GAL4 reporter protein. We report that direct stimulation of AMPAR increases non-amyloidogenic α-secretase-mediated APP processing and inhibits Aβ production. Processing was blocked by the matrix metalloproteinase inhibitor TAPI-1 but was only partially dependent on Ca(2+) influx and ERK activity. AMPAR can therefore, be added to the repertoire of receptors that couple to non-amyloidogenic APP processing at glutamatergic synapses and thus pharmacological targeting of AMPAR could potentially influence the development and progression of Aβ pathology in AD.
PLoS ONE 10/2013; 8(10):e78155. DOI:10.1371/journal.pone.0078155 · 3.23 Impact Factor
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