Project description
Understanding Alzheimer’s disease mechanisms
Alzheimer’s disease (AD) is the leading cause of dementia, imposing substantial socio-economic burdens. Given the absence of a cure, understanding disease mechanisms and developing new therapies is crucial. Inhibiting prostaglandin 2 (PGE2) signalling, specifically PGE2 receptor 2 (EP2), has restored youthful hippocampal functions in ageing mice, but its specific impact on AD-related deficits remains unclear. The MSCA-funded immuno-ALZ project aims to study the effects of EP2 inhibition on cognitive decline in an APP-KI mouse model of AD. The project will compare brain-penetrant and non-brain-penetrant EP2 antagonists and assess their impact on memory, synaptic function, glucose metabolism, brain inflammation, and AD-like pathology spread. The study will involve behavioural tests, biochemical analyses, and live imaging.
Objective
Background and rationale: Alzheimer's disease (AD) is the main cause of dementia, with substantial socio-economic burdens. Due to the absence of a cure, understanding disease mechanisms and developing new therapies is crucial. Age-related systemic and brain inflammation contributes to cognitive decline. Inhibiting prostaglandin 2 (PGE2) - PGE2 receptor 2 (EP2) signalling has restored youthful hippocampal functions in ageing mice, but its specific impact on AD-related deficits remains unclear. Aim: We seek to explore the effect of EP2 inhibition on bioenergetic and cognitive decline in an amyloid precursor protein knock-in (APP-KI) mouse model of AD, using neurobiology, immunology and data science. Objective 1: We will compare the effects of brain-penetrant and non-brain-penetrant EP2 antagonists on memory, synaptic function, glucose metabolism, systemic/brain inflammation and amyloid-beta (A) pathology. Objective 2: We will study these effects in APP-KI mice injected with AD brain-derived pathological tau. We will then assess the impact of peripheral immune modulation on AD-like pathology spread. Objective 3: We will analyse the changes and interplay among synaptic dynamics, microglial activity, A/tau pathology progression after EP2 inhibition via real-time imaging. Methodology: The study will involve various assessments, including behavioural tests, biochemical and immunohistochemical analyses, multianalyte assays, as well as multi-omics approaches that combine transcriptomics and metabolomics. Additionally, it will utilise two- and three-photon microscopy for live imaging. Expected results: We anticipate gaining valuable insights into a) PGE2-EP2 inhibition effects on AD-driven deficits, and b) whether peripheral immune re-programming restores brain functions beyond the blood-brain barrier. Impact: The project could yield novel mechanistic and translational outcomes, guiding non-invasive therapeutic approaches to combat AD through peripheral modulations.
Fields of science (EuroSciVoc)
CORDIS classifies projects with EuroSciVoc, a multilingual taxonomy of fields of science, through a semi-automatic process based on NLP techniques.
CORDIS classifies projects with EuroSciVoc, a multilingual taxonomy of fields of science, through a semi-automatic process based on NLP techniques.
- natural sciencesbiological sciencesneurobiology
- medical and health sciencesbasic medicineneurologydementiaalzheimer
- natural sciencesphysical sciencesopticsmicroscopy
- medical and health sciencesbasic medicineimmunology
- medical and health sciencesbasic medicinepathology
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Keywords
Programme(s)
- HORIZON.1.2 - Marie Skłodowska-Curie Actions (MSCA) Main Programme
Funding Scheme
HORIZON-TMA-MSCA-PF-GF - HORIZON TMA MSCA Postdoctoral Fellowships - Global FellowshipsCoordinator
4365 ESCH-SUR-ALZETTE
Luxembourg