Mechanistic dissection of iron processing in neurovascular cells and its contribution to the development of Alzheimer’s disease

• Applicants: Professor Dr. Steffen Roßner; Bilal Sheikh, Ph.D.
• Subject Area: Molecular and Cellular Neurology and Neuropathology
• Term: since 2026
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 575806918

Alzheimer’s disease (AD) is a major health problem, with 1 in 9 people over the age of 65 presenting with AD. There are currently no cures and only limited treatment options for AD, highlighting the urgent need to better understand the molecular mechanisms promoting the onset and progression of AD. The brain is separated from general circulation by the blood-brain-barrier (BBB), which consists of endothelial cells (ECs), pericytes and astrocytic endfeet. Neurovascular breakdown is strongly correlated with AD symptoms and cognitive decline in human patients, while vascular defects in animal models accelerate the development of AD pathology. Thus, improving neurovascular function is a promising avenue to impede the development and progression of AD. However, to date, the molecular mechanisms that maintain the health or trigger the breakdown of neural vessels remain poorly understood. In our preliminary work, we undertook scRNA-seq analyses of neurovascular cells from young Tg2576 mice to uncover early molecular events during AD onset. We uncovered ferritin light chain (Ftl) as the strongest upregulated gene in the EC and pericyte compartments in Tg2576 mouse brains. FTL is a core component of ferritin, which stores intracellular iron and facilitates its transport across the endothelium. Complementary analyses of human brains from patients with AD and vascular dementia (VAD) confirmed the increased expression of FTL in vascular cells in human AD and VAD pathology. In ex vivo systems, over-expression of FTL in ECs triggered breakdown of the vascular barrier, while knockdown of FTL led to improved vascular barrier function, suggesting an important cell intrinsic role for FTL in the brain EC compartment and AD pathophysiology. In the proposed project, we aim to utilise a combination of human AD samples and AD animal models to mechanistically dissect the role of FTL in brain ECs. By manipulating FTL expression specifically in brain ECs in vivo in AD models, our proposed experiments will identify the importance of FTL in maintaining neurovascular function, as well as its impact on amyloid pathology, cognition and molecular networks that control the health of neural vessels. Through our multidisciplinary and mechanistic approach, our work will reveal novel insights into how FTL and iron homeostasis in ECs contributes to neurovascular health. Given the high prevalence of AD in our community and the central role of neurovascular breakdown in AD pathology, our work promises to reveal novel strategies to improve neurovascular function and ultimately, impede AD progression.

• DFG Programme: Research Grants