The ß-amyloid peptide compromises Reelin signaling in Alzheimer's disease.
Por:
Cuchillo-Ibañez I, Mata-Balaguer T, Balmaceda V, Arranz JJ, Nimpf J and Saez J
Publicada:
17 ago 2016
Categoría:
Multidisciplinary
Resumen:
Reelin is a signaling protein that plays a crucial role in synaptic function, which expression is influenced by ß-amyloid (Aß). We show that Reelin and Aß oligomers co-immunoprecipitated in human brain extracts and were present in the same size-exclusion chromatography fractions. Aß treatment of cells led to increase expression of Reelin, but secreted Reelin results trapped together with Aß 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, Aß 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 Aß hinders its biological activity.
Filiaciones:
:
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
Mata-Balaguer T:
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
Balmaceda V:
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
Arranz JJ:
Departamento Producción Animal, Universidad de León, León, Spain
Nimpf J:
Department of Medical Biochemistry, Max F. Perutz Laboratories, Medical University of Vienna, 1030 Vienna, Austria
Saez J:
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
Open Access
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