Description du projet
Un regard sans précédent sur la pathologie du stade précoce de la maladie d’Alzheimer
La maladie d’Alzheimer (MA) est un trouble neurologique progressif et la cause la plus fréquente de démence. Les échantillons de tissus humains représentant les premiers stades de la maladie faisant défaut, les premiers mécanismes moléculaires de la MA sont mal compris. Les microglies, des cellules spécialisées du cerveau, joueraient un rôle majeur dans le dysfonctionnement neuronal et le déclin cognitif. Le projet pionnier HUMANE, financé par l’UE, étudiera ce phénomène au stade précoce de la MA à l’aide d’un échantillon unique de tissu cérébral provenant de certains patients présentant une pathologie précoce de la MA dans le cadre d’une affection distincte. Les résultats pourraient ouvrir la voie à de potentielles cibles thérapeutiques ainsi qu’à des biomarqueurs de la maladie.
Objectif
The molecular mechanisms leading to Alzheimer's disease (AD) are poorly understood. This is due to lack of human tissue samples for research representing early changes of AD pathology. The accumulating pathology, including beta-amyloid and tau proteins, are manifested by concomitant neuroinflammatory reactions geared by malfunctional microglia. Microglia in the human and mouse AD brain exist in various subpopulations from which a specific, disease-associated microglia population is thought to be involved in AD pathogenesis. However, there is no evidence on whether and how these specific microglial subpopulations actually impair neuronal functions in human AD brain. I will now assess neuron-glia network activities and functions indicative of early AD pathology in humans. I hypothesize that early AD pathology selectively impairs neuronal circuits and that glial cells, especially specific microglia subpopulations, contribute to neuronal dysfunction and cognitive decline. These events contribute to a detectable vesicle-based biomarker profile in cerebrospinal fluid and blood prior the clinical disease. Due to early AD pathology present in a subpopulation of idiopathic normal pressure hydrocephalus (iNPH) patients, the brains of the iNPH patients offer a unique window to evaluate cellular and molecular events occurring during early AD. I combine a series of state-of-the art techniques to answer how and what glial cell subpopulations are associated with altered neuronal network activities at subcellular and spatial resolution in human brain impacted by early AD-related pathology. Novel methodologies established in my lab, knowhow and access to unique brain samples make me uniquely positioned to form a holistic view on how early AD-pathology impacts cellular functions at multiple levels. This will pinpoint novel molecular targets for further validation and new fluid biomarkers.
Champ scientifique
- medical and health sciencesbasic medicineneurologydementiaalzheimer
- natural sciencesbiological sciencesbiochemistrybiomoleculesproteins
- natural sciencesbiological sciencescell biology
- medical and health sciencesbasic medicinepathology
- natural sciencesbiological sciencesmolecular biologymolecular neuroscience
Mots‑clés
Programme(s)
- HORIZON.1.1 - European Research Council (ERC) Main Programme
Régime de financement
HORIZON-ERC - HORIZON ERC GrantsInstitution d’accueil
70211 KUOPIO
Finlande