Name of Fellow

    Santiago Sole Domenech



    Contact information of fellow



    Title of project/programme

    Alzheimer´s amyloid degradation by secreted lysosomal enzymes

    Source of funding information

    Total sum awarded (Euro)

    € 342,764

    Start date of award


    Total duration of award in years


    The project/programme is most relevant to:

    Alzheimer's disease & other dementias


    amyloid degradation | microglia lysosomes | lysosomal acidity | brain imaging | lysosomal synapse

    Research Abstract

    Alzheimer disease (AD) is the most common form of dementia, affecting 25 million individuals worldwide. Some degenerating brain areas present increased amyloid-beta (Ab) production, leading to Ab plaque formation. It is unclear how microglia, the main immune cells of the brain, degrade plaques that are significantly larger than the cells themselves. Our hypothesis is that microglia can secrete lysosomal enzymes upon contact with Ab and create an extracellular digestive compartment, the lysosomal synapse, that helps to break down the Ab plaque, as we have previously seen in macrophages encountering large aggregated LDL deposits. In order to visualize the lysosomal synapse in vitro and in vivo and determine its acidic properties, novel pH probes selectively uptaken by microglia lysosomes will be tested in cell cultures and in AD model mice, and visualized using confocal and live imaging multiphoton microscopy. Next, we will investigate the mechanisms that regulate lysosomal activity in macrophages and microglia using molecular biology and siRNA techniques, as our previous work demonstrated that acidification of microglia lysosomes enhances Ab degradation. The main aim of this project is to obtain data about the mechanisms of microglia lysosomal secretion and the role of extracellular hydrolysis of Ab by lysosomal enzymes, with the long term goal of developing non-inflammatory therapies aiming at enhancing brain Ab degradation in AD patients as an alternative to Ab immunization

Types: Fellowships
Member States: Sweden
Diseases: Alzheimer's disease & other dementias
Years: 2016
Database Categories: N/A
Database Tags: N/A

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