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Beta-amyloid impairs reelin signaling.

ABSTRACT: Reelin is a signaling protein increasingly associated with the pathogenesis of Alzheimer's disease that relevantly modulates tau phosphorylation. We have previously demonstrated that ?-amyloid peptide (A?) alters reelin expression. We have now attempted to determine whether abnormal reelin triggered by A? will result in signaling malfunction, contributing to the pathogenic process. Here, we show that reelin forms induced by ?-amyloid are less capable of down-regulating tau phosphorylation via disabled-1 and GSK3? kinase. We also demonstrate that the scaffold protein 14-3-3 that increases tau phosphorylation by modulating GSK3? activity, is up-regulated during defective reelin signaling. Binding of reelin to its receptor, mainly ApoER2 in the brain, relays the signal into the cell. We associate the impaired reelin signaling with inefficiency of reelin in forming active homodimers and decreased ability to bind efficiently to its receptor, ApoER2. More remarkably, reelin from Alzheimer cortex shows a tendency to form large complexes instead of homodimers, the active form for signaling. Our results suggest that reelin expression is altered by A? leading to impaired reelin signaling.

SUBMITTER: Cuchillo-Ibanez I

PROVIDER: S-EPMC3741172 | biostudies-literature | 2013

REPOSITORIES: biostudies-literature

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Beta-amyloid impairs reelin signaling.

Cuchillo-Ibáñez Inmaculada I Balmaceda Valeria V Botella-López Arancha A Rabano Alberto A Avila Jesus J Sáez-Valero Javier J

PloS one 20130812 8

Reelin is a signaling protein increasingly associated with the pathogenesis of Alzheimer's disease that relevantly modulates tau phosphorylation. We have previously demonstrated that β-amyloid peptide (Aβ) alters reelin expression. We have now attempted to determine whether abnormal reelin triggered by Aβ will result in signaling malfunction, contributing to the pathogenic process. Here, we show that reelin forms induced by β-amyloid are less capable of down-regulating tau phosphorylation via di ...[more]

PMID: 23951306

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Project description:Projection neurons in the anteriolateral part of entorhinal cortex layer II are the predominant cortical site for hyper-phosphorylation of tau and formation of neurofibrillary tangles in prodromal Alzheimer's disease. A majority of layer II projection neurons in anteriolateral entorhinal cortex are unique among cortical excitatory neurons by expressing the protein reelin. In prodromal Alzheimer's disease, these reelin-expressing neurons are prone to accumulate intracellular amyloid-β, which is mimicked in a rat model that replicates the spatio-temporal cascade of the disease. Two important findings in relation to this are that reelin-signalling downregulates tau phosphorylation, and that oligomeric amyloid-β interferes with reelin-signalling. Taking advantage of this rat model, we used proximity ligation assay to assess whether reelin and intracellular amyloid-β directly interact during early, pre-plaque stages in anteriolateral entorhinal cortex layer II reelin-expressing neurons. We next made a viral vector delivering micro-RNA against reelin, along with a control vector, and infected reelin-expressing anteriolateral entorhinal cortex layer II-neurons to test whether reelin levels affect levels of intracellular amyloid-β and/or amyloid precursor protein. We analysed 25.548 neurons from 24 animals, which results in three important findings. First, in reelin-expressing anteriolateral entorhinal cortex layer II-neurons, reelin and intracellular amyloid-β engage in a direct protein-protein interaction. Second, injecting micro-RNA against reelin lowers reelin levels in these neurons, amounting to an effect size of 1.3-4.5 (Bayesian estimation of Cohen's d effect size, 95% credible interval). This causes a concomitant reduction of intracellular amyloid-β ranging across three levels of aggregation, including a reduction of Aβ42 monomers/dimers amounting to an effect size of 0.5-3.1, a reduction of Aβ prefibrils amounting to an effect size of 1.1-3.5 and a reduction of protofibrils amounting to an effect size of 0.05-2.1. Analysing these data using Bayesian estimation of mutual information furthermore reveals that levels of amyloid-β are dependent on levels of reelin. Third, the reduction of intracellular amyloid-β occurs without any substantial associated changes in levels of amyloid precursor protein. We conclude that reelin and amyloid-β directly interact at the intracellular level in the uniquely reelin-expressing projection neurons in anteriolateral entorhinal cortex layer II, where levels of amyloid-β are dependent on levels of reelin. Since amyloid-β is known to impair reelin-signalling causing upregulated phosphorylation of tau, our findings are likely relevant to the vulnerability for neurofibrillary tangle-formation of this entorhinal neuronal population.

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Beta-amyloid impairs reelin signaling.

Publications

Beta-amyloid impairs reelin signaling.

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