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The epigenetic regulation of reelin in Alzheimer's disease

16th national competition for scientific and technical research

The genome and epigenome

Senior Researcher : Javier Sáez Valero

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Research Centre or Institution : Instituto de Neurociencias. CSIC-Universidad Miguel Hernández. Alicante.


The group was the first to demonstrate the anomalous expression of the glycoprotein Reeline in Alzheimer's disease (AD), which may indicate its possible participation in the aetiology of the disease. The levels of Reeline increase in the presence of the β amyloide peptide (or Aβ) effector of Alzheimer's; when the expression of Reeline is altered in the AD brain, with increased levels of transcription. This project has the aim of examining the possible epigenetic regulation of Reeline in AD, mainly through the state of methylation of its promoter, and the influence that Aβ may have on the same. However, the β‑amyloide may also modulate genetic expression through other routes. The known β‑amyloide precursor (APP), when it is processed by enzymes known as secretases to generate Aβ, may also produce intracellular fragments. ICD (the intracellular domain of terminal carboxyl) of the APP has been proposed as a transcription regulator. Curiously, the Reeline receptors, mainly ApoER2 in the brain, are also processed by secretases following their binding with the ligand, Reeline. Work has recently taken place to characterise the processing of ApoER2 after its binding to Reeline, and particularly the generation of its ICD. The generation of an ICD of ApoER2 has been described after binding to its ligand, as able to modulate the genetic expression of Reeline itself. This result is somewhat unexpected, given that canonically Reeline is understood to have a "paracrine" effect, being secreted by certain cells and exercising an effect on other target cells (which express the ligand); however, many cells that express ApoER2 also express Reeline. The results also show that the protein preseniline‑1 (PS1), a catalytic subunit of the γ‑secretase complex and the final effector of the processing of APP and ApoER2, is the key in this regulation.

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