Descrizione del progetto
Uno sguardo inedito alla patologia della malattia di Alzheimer in fase iniziale
La malattia di Alzheimer è un disturbo neurologico progressivo e la causa più comune di demenza. I meccanismi molecolari precoci dell’Alzheimer sono poco conosciuti a causa della mancanza di campioni di tessuto umano che rappresentino le prime fasi della malattia. Quello che si pensa è che la microglia, cellule specializzate del cervello, svolga un ruolo fondamentale nella disfunzione neuronale e nel declino cognitivo. Il progetto pionieristico HUMANE, finanziato dall’UE, studierà questo aspetto nell’Alzheimer in fase iniziale, utilizzando un campione unico di tessuto cerebrale di alcuni pazienti che presentano una patologia di Alzheimer precoce come parte di un altro disturbo. I risultati potrebbero indicare potenziali bersagli terapeutici e biomarcatori della malattia.
Obiettivo
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.
Campo scientifico
- medical and health sciencesbasic medicineneurologydementiaalzheimer
- natural sciencesbiological sciencesbiochemistrybiomoleculesproteins
- natural sciencesbiological sciencescell biology
- medical and health sciencesbasic medicinepathology
- natural sciencesbiological sciencesmolecular biologymolecular neuroscience
Parole chiave
Programma(i)
- HORIZON.1.1 - European Research Council (ERC) Main Programme
Argomento(i)
Meccanismo di finanziamento
HORIZON-ERC - HORIZON ERC GrantsIstituzione ospitante
70211 KUOPIO
Finlandia