The ?-amyloid peptide compromises Reelin signaling in Alzheimer's disease.
Reelin is a signaling protein that plays a crucial role in synaptic function, which expression is influenced by ?-amyloid (A?). We show that Reelin and A? oligomers co-immunoprecipitated in human brain extracts and were present in the same size-exclusion chromatography fractions. A? treatment of cells led to increase expression of ... Reelin, but secreted Reelin results trapped together with A? 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, A? 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 A? hinders its biological activity.
Mesh Terms:
Adaptor Proteins, Signal Transducing, Aged, Aged, 80 and over, Alzheimer Disease, Amyloid beta-Peptides, Amyloid beta-Protein Precursor, Animals, Brain, Case-Control Studies, Cell Adhesion Molecules, Neuronal, Cell Line, Extracellular Matrix Proteins, Female, Humans, LDL-Receptor Related Proteins, Male, Middle Aged, Mutation, Nerve Tissue Proteins, Peptide Fragments, Phosphorylation, Protein Binding, RNA, Messenger, Recombinant Proteins, Serine Endopeptidases, Sheep, Sheep Diseases, Sheep, Domestic, Signal Transduction
Adaptor Proteins, Signal Transducing, Aged, Aged, 80 and over, Alzheimer Disease, Amyloid beta-Peptides, Amyloid beta-Protein Precursor, Animals, Brain, Case-Control Studies, Cell Adhesion Molecules, Neuronal, Cell Line, Extracellular Matrix Proteins, Female, Humans, LDL-Receptor Related Proteins, Male, Middle Aged, Mutation, Nerve Tissue Proteins, Peptide Fragments, Phosphorylation, Protein Binding, RNA, Messenger, Recombinant Proteins, Serine Endopeptidases, Sheep, Sheep Diseases, Sheep, Domestic, Signal Transduction
Sci Rep
Date: Dec. 17, 2015
PubMed ID: 27531658
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