Project description
An unprecedented look at the pathology of early-stage Alzheimer’s disease
Alzheimer’s disease (AD) is a progressive neurologic disorder and the most common cause of dementia. The early molecular mechanisms of AD are poorly understood due to a lack of human tissue samples representing early disease stages. Microglia, specialised cells in the brain, are thought to play a leading role in neuronal dysfunction and cognitive decline. The pioneering EU-funded HUMANE project will investigate this in early-stage AD using a unique sample of brain tissue from certain patients showing early AD pathology as part of a separate condition. Outcomes could point the way to potential therapeutic targets and disease biomarkers.
Objective
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.
Fields of science
- medical and health sciencesbasic medicineneurologydementiaalzheimer
- natural sciencesbiological sciencesbiochemistrybiomoleculesproteins
- natural sciencesbiological sciencescell biology
- medical and health sciencesbasic medicinepathology
- natural sciencesbiological sciencesmolecular biologymolecular neuroscience
Keywords
Programme(s)
- HORIZON.1.1 - European Research Council (ERC) Main Programme
Funding Scheme
HORIZON-ERC - HORIZON ERC GrantsHost institution
70211 KUOPIO
Finland