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Research Group
Altered molecular mechanism in Alzheimer’s disease and dementia
Unit Unit Molecular Neurobiology »

Principal Investigator Ph.D. Investigator Graduate students / Research Assistant Technician
Research Fields
Our aim is to introduce a research line into Alzheimer’s disease (AD) and dementia that originated from a basic point of view but that is relevant to the development of clinical-diagnostic applications. Therefore, the translational benefits of our research lie in the fact that we not only aim to clarify the pathological mechanisms behind these diseases, but also to define potential diagnostic tools and/or processes with therapeutic relevance.

In recent years, we have been involved in studying how β-amyloid influences the expression of acetylcholinesterase (AChE, a key enzyme of the cholinergic system). In addition, we have described for the first time a direct association between presenilin 1 (PS1, a key enzyme in the proteolytic processing of amyloid protein precursor) and AChE, which may be relevant for the pathological progress of dementia and the design of therapeutic strategies.

We are also pioneers in describing an altered expression and glycosylation patterns of the glycoprotein Reelin in AD. Reelin is a signaling protein that modulates synaptic function and plasticity in the mature brain, thereby favouring memory formation. Our effort is to demonstrate a novel mechanism by which β-amyloid regulates Reelin expression, thereby influencing its signaling cascade that ultimately controls tau phosphorylation.

Furthermore, we evaluate the diagnostic potential and methodological approaches for analysis of particular glycoforms of proteins, which improve sensitivity and specificity of the biomarkers. We also develop assays to identify secretase-related proteins, related with β-amyloid metabolism, in the cerebrospinal fluid. We also have collaborated in the BiomarkAPD project (a JPND initiative of the UE) and the Society for CSF analysis and clinical neurochemistry in the validation and standardization of CSF biomarkers.
γ-Secretase inhibitors (GSIs) are potential therapeutic agents AD, however, trials have proven disappointing. Recently, we tested how GSIs affect PS1 levels in cellular and animal models. As such, we provide evidence that γ-secretase inhibition could provoke a rebound increase in PS1, which may be of particular importance for the design of specific AD therapies based on GSIs and related drugs.

Our group is a foundational member of the CIBERNED (Center for Networked Biomedical Research focused in neurodegenerative diseases, ISC-III, Spain).

Representative Publications

Sogorb-Esteve A , García-Ayllón MS, Llansola M, Felipo V, Blennow K, Sáez-Valero J. " Inhibition of γ-Secretase Leads to an Increase in Presenilin-1. " Mol Neurobiol . [Epub ahead of print] , - Aug 16 ( 2017 )

García-Ayllón MS , López-Font I, Boix CP, Fortea J, Sánchez-Valle R, Lleó A, Molinuevo JL, Zetterberg H, Blennow K, Sáez-Valero J. " C-terminal fragments of the amyloid precursor protein in cerebrospinal fluid as potential biomarkers for Alzheimer disease. 7: 2477. 2017. " Sci Rep . 7 , - 2477 ( 2017 )

Sogorb-Esteve A , García-Ayllón MS, Fortea J, Sánchez-Valle R, Lleó A, Molinuevo JL, Sáez-Valero J. " Cerebrospinal fluid Presenilin-1 increases at asymptomatic stage in genetically determined Alzheimer's disease. " Mol Neurodegener . 11 , - 66 ( 2016 )

Cuchillo-Ibañez I , Mata-Balaguer T, Balmaceda V, Arranz JJ, Nimpf J, Sáez-Valero J. " The β-amyloid peptide compromises Reelin signaling in Alzheimer’s Disease. " . 6 , - 31646 ( 2016 )

Cuchillo-Ibañez I. , Lopez-Font I, Boix-Amorós A, Brinkmalm G, Blennow K, Molinuevo JL, Sáez-Valero J. " Heteromers of amyloid precursor protein in cerebrospinal fluid. " Mol Neurodegener . 10 , 2 - 2 ( 2015 )
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