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Projects. Life and Earth Sciences

The epigenetic regulation of reelin in Alzheimer's disease

Lead Researcher:
Javier Sáez Valero

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

Synopsis: 

Javier Sáez ValeroThe 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.

 

Researcher's web address:
http://in.umh.es/es/personal-detalle.aspx?personal=47

 


Javier Sáez Valero

Dr. Sáez Valero graduated in Biology from the University of Murcia, and he received his PhD from the same university in 1996. In the same year of 1996 and by means of a grant from the Ramón Areces Foundation, he started a Postdoctoral stay of two and a half years in the Pathology Dept. of the University of Melbourne, where he studied several interactions between β-amyloid and acetylcholinesterase enzyme, with implications that run from therapy to diagnosis. He returned to Europe in 2009, where in postdoctoral studies at the Mario Negri Institute, Milan, he researched toxicity and death due to apoptosis of β-amyloid and the prion peptide. Since 2001, he has directed his research group in the Neuroscience Institute of the Miguel Hernández University, of which he is tenured professor. In 2006 he joined CIBERNED, a recently created online research institute which has the aim of bringing together basic and clinical research groups with an interest in neurodegenerative diseases such as Alzheimer's. Dr. Sáez Valero has dedicated his research work to the investigation of pathologies of the nervous system, with works on cerebral ischaemia, prion disease and hepatic encephalopathy, but above all Alzheimer's, with more than 40 papers published in this field. He is currently trying to advance knowledge about the relationship between abnormal amyloid metabolism and cholinergic regulation; as well as the interrelationship between the amyloid itself and the other event which triggers Alzheimer's disease, the anomalous phosphorylation of tau, together with the role of reelin glycoprotein in the said interrelationship. He also has a line of research into diagnostic markers of Alzheimer's disease. In 2005, he received the "Idea" Prize for Basic Science from the City of Arts and Sciences Foundation for his project in the area of Alzheimer's disease.


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