immuno-ALZ | Modulating immune responses to mitigate neuroinflammation, bioenergetic decrease and cognitive decline in Alzheimer’s disease

Summary
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 (Aβ) 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, Aβ/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.
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More information & hyperlinks
Web resources: https://cordis.europa.eu/project/id/101154748
Start date: 01-03-2025
End date: 29-02-2028
Total budget - Public funding: - 266 684,00 Euro
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Original description

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 (Aβ) 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, Aβ/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.

Status

SIGNED

Call topic

HORIZON-MSCA-2023-PF-01-01

Update Date

06-11-2024
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Horizon Europe
HORIZON.1 Excellent Science
HORIZON.1.2 Marie Skłodowska-Curie Actions (MSCA)
HORIZON.1.2.0 Cross-cutting call topics
HORIZON-MSCA-2023-PF-01
HORIZON-MSCA-2023-PF-01-01 MSCA Postdoctoral Fellowships 2023