Molecular mechanisms of lipoprotein (dys)metabolism in the central nervous system

• Applicant: Professor Dr. Mikael Jakob Simons
• Subject Area: Molecular and Cellular Neurology and Neuropathology ; Molecular Biology and Physiology of Neurons and Glial Cells
• Term: since 2026
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 563286456

Lipid transport and distribution within the brain are managed by lipoprotein particles, assemblies of lipids and apolipoproteins. However, the mechanisms governing lipoprotein transport between cells and the specific cargo they carry remain poorly understood. Neurodegenerative diseases are associated with increased production of lipoproteins, yet the molecular structure and ultimate fate of these particles are still unclear. In this project, we will generate novel tool that will enable in situ cell biology to analyze lipoprotein trafficking between the different cell types with unparalleled sensitivity and specificity, applicable to both normal physiology and pathological conditions. We propose that, in a healthy brain, lipoprotein particles, primarily synthesized by astrocytes, are transported to oligodendrocytes and neurons to support critical processes such as synaptogenesis and myelination. With aging, we suggest that a shift occurs in the composition and metabolism of these lipoproteins, redirecting them to microglia, where they are taken up into the endo-lysosomal system, aggregate, and initiate a pathological cascade culminating in Aβ amyloidosis. Such a shift in lipoprotein trafficking is the basis of atherosclerosis, and we propose here that it could also serve as the starting point in the pathological cascade leading to amyloidosis in Alzheimer’s disease. To test this model, we plan to investigate the biology of lipoprotein particles in young and aged healthy brains, as well as in diseased brains, to map their trafficking pathways, receptor interactions, and associations with pathology.

• DFG Programme: Reinhart Koselleck Projects