title: The β-amyloid peptide compromises Reelin signaling in Alzheimer's disease.
abstract: Reelin is a signaling protein that plays a crucial role in synaptic function, which expression is influenced by β-amyloid (Aβ). We show that Reelin and Aβ oligomers co-immunoprecipitated in human brain extracts and were present in the same size-exclusion chromatography fractions. Aβ treatment of cells led to increase expression of Reelin, but secreted Reelin results trapped together with Aβ aggregates. In frontal cortex extracts an increase in Reelin mRNA, and in soluble and insoluble (guanidine-extractable) Reelin protein, was associated with late Braak stages of Alzheimer's disease (AD), while expression of its receptor, ApoER2, did not change. However, Reelin-dependent induction of Dab1 phosphorylation appeared reduced in AD. In cells, Aβ reduced the capacity of Reelin to induce internalization of biotinylated ApoER2 and ApoER2 processing. Soluble proteolytic fragments of ApoER2 generated after Reelin binding can be detected in cerebrospinal fluid (CSF). Quantification of these soluble fragments in CSF could be a tool to evaluate the efficiency of Reelin signaling in the brain. These CSF-ApoER2 fragments correlated with Reelin levels only in control subjects, not in AD, where these fragments diminished. We conclude that while Reelin expression is enhanced in the Alzheimer's brain, the interaction of Reelin with Aβ hinders its biological activity.
authors.affiliation: Instituto de Neurociencias de Alicante, Universidad Miguel Hernández-CSIC, Sant Joan d'Alacant, E-03550, Spain.|Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), Spain.
authors.forename: Inmaculada
authors.initials: I
authors.lastname: Cuchillo-Ibañez
authors.affiliation: Instituto de Neurociencias de Alicante, Universidad Miguel Hernández-CSIC, Sant Joan d'Alacant, E-03550, Spain.|Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), Spain.
authors.forename: Trinidad
authors.initials: T
authors.lastname: Mata-Balaguer
authors.affiliation: Instituto de Neurociencias de Alicante, Universidad Miguel Hernández-CSIC, Sant Joan d'Alacant, E-03550, Spain.|Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), Spain.
authors.forename: Valeria
authors.initials: V
authors.lastname: Balmaceda
authors.affiliation: Departamento Producción Animal, Universidad de León, León, Spain.
authors.forename: Juan José
authors.initials: JJ
authors.lastname: Arranz
authors.affiliation: Department of Medical Biochemistry, Max F. Perutz Laboratories, Medical University of Vienna, 1030 Vienna, Austria.
authors.forename: Johannes
authors.initials: J
authors.lastname: Nimpf
authors.affiliation: Instituto de Neurociencias de Alicante, Universidad Miguel Hernández-CSIC, Sant Joan d'Alacant, E-03550, Spain.|Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), Spain.
authors.forename: Javier
authors.initials: J
authors.lastname: Sáez-Valero
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism; D000368:Aged; D000369:Aged, 80 and over; D000544:Alzheimer Disease / Q000209:etiology / Q000235:genetics / Q000378:metabolism*; D016229:Amyloid beta-Peptides / Q000378:metabolism*; D016564:Amyloid beta-Protein Precursor / Q000378:metabolism; D000818:Animals; D001921:Brain / Q000378:metabolism; D016022:Case-Control Studies; D015816:Cell Adhesion Molecules, Neuronal / Q000235:genetics / Q000378:metabolism*; D002460:Cell Line; D016326:Extracellular Matrix Proteins / Q000235:genetics / Q000378:metabolism*; D005260:Female; D006801:Humans; D026502:LDL-Receptor Related Proteins / Q000134:cerebrospinal fluid / Q000235:genetics / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D009154:Mutation; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism*; D010446:Peptide Fragments / Q000378:metabolism; D010766:Phosphorylation; D011485:Protein Binding; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D011994:Recombinant Proteins / Q000235:genetics / Q000378:metabolism; D000091042:Reelin Protein; D012697:Serine Endopeptidases / Q000235:genetics / Q000378:metabolism*; D012756:Sheep; D012757:Sheep Diseases / Q000235:genetics / Q000378:metabolism; D034561:Sheep, Domestic; D015398:Signal Transduction
chemical_list: C545487:APP protein, human; D048868:Adaptor Proteins, Signal Transducing; D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; D015816:Cell Adhesion Molecules, Neuronal; C115785:DAB1 protein, human; D016326:Extracellular Matrix Proteins; D026502:LDL-Receptor Related Proteins; D009419:Nerve Tissue Proteins; D010446:Peptide Fragments; D012333:RNA, Messenger; D011994:Recombinant Proteins; D000091042:Reelin Protein; C098773:low density lipoprotein receptor-related protein 8; C000717127:RELN protein, human; D012697:Serine Endopeptidases