Dinkel, L. | Search bioRxiv

bioRxiv2024

The late onset Alzheimer's disease risk factor iRhom2/RHBDF2 is a modifier of microglial TREM2 proteolysis

The cell surface receptor TREM2 is a key genetic risk factor and drug target in Alzheimers disease (AD). In the brain, TREM2 is expressed in microglia, where it undergoes proteolytic cleavage, linked to AD risk, but the responsible protease in microglia is still unknown. Another microglia-expressed AD risk factor is catalytically inactive rhomboid 2 (iRhom2, RHBDF2), which binds to and acts as a non-catalytic subunit of the metalloprotease ADAM17. A potential role in TREM2 proteolysis is not yet known. Using microglial-like BV2 cells, bone marrow-derived macrophages and primary murine microglia, we identify iRhom2 as a modifier of ADAM17-mediated TREM2 shedding. Loss of iRhom2 increased TREM2 in cell lysates and at the cell surface and enhanced TREM2 signaling and microglial phagocytosis of the amyloid {beta}-peptide (A{beta}). This study establishes ADAM17 as a physiological TREM2 protease in microglia, and suggests iRhom2 as a potential drug target for modulating TREM2 proteolysis in AD.

biochemistry↗

bioRxiv2019

Loss of NPC1 enhances phagocytic uptake and impairs lipid trafficking in microglia

Niemann-Pick type C disease is a rare neurodegenerative disorder mainly caused by mutations in Npc1, resulting in abnormal late endosomal/lysosomal lipid storage. Although microgliosis is a prominent pathological feature, consequences of NPC1 loss on microglial function remain uncharacterized. Here, we provide an in-depth characterization of microglial proteomic signatures and phenotypes in a NPC1-deficient (Npc1-/-) murine model and patient blood-derived macrophages. We demonstrate enhanced phagocytic uptake and impaired lipid trafficking in Npc1-/- microglia that precede neuronal death. Loss of NPC1 compromises microglial developmental functions as revealed by increased synaptic pruning and deficient myelin turnover. Undigested myelin accumulates within multi-vesicular bodies of Npc1-/- microglia while lysosomal degradation remains preserved. To translate our findings to human disease, we generated novel ex vivo assays using patient macrophages that displayed similar proteomic disease signatures and lipid trafficking defects as murine Npc1-/- microglia. Thus, peripheral macrophages provide a novel promising clinical tool for monitoring disease progression and therapeutic efficacy in NPC patients. Our study underscores an essential role for NPC1 in immune cells and implies microglial therapeutic potential.

neuroscience↗