An immune response is part of most neurological diseases, and the development of late-onset Alzheimer's Disease (AD) has been linked to immune related genes and most recently also to epigenetic modifications. This indicates a significant contribution of immunity to AD pathology. The immune response during AD is largely mediated by the brain's resident macrophages, the microglia, which are attracted to and surround Aβ deposits in the AD brain. However, various aspects of their role in amyloid plaque homeostasis and AD pathogenesis remain unclear. Furthermore, how inflammation in the periphery may affect the immune response in the brain remains incompletely understood.
1. To understand how microglia contribute to AD pathology and in particular to Aβ plaque formation and Aβ clearance.
2. To investigate how peripheral inflammatory stimuli alter central immunity, and how this may affect the pathogenesis of AD as well as other neurodegenerative diseases and stroke.
To this end we analyze Aβ precursor protein- (APP) transgenic mouse lines that are deficient in a variety of immune-related molecules, that allow the temporary ablation of microglia, or after peripheral immune stimulation. We isolate microglia from adult and aged brains and study their phagocytic behavior and inflammatory responses in culture. Together with the molecular imaging group we use multiphoton imaging to study microglial behavior in the aging brain and in APP transgenic mice.
In the Neuroimmunology group, we previously found that short-term ablation (3-4 weeks) of microglia in APP x CD11b-HSVTK mice did not significantly affect plaque homeostasis (Grathwohl et al., Nat Neurosci 2009). Interestingly, when analyzing the CD11b-HSVTK strain, we found that the microglia-depleted brain is rapidly repopulated by peripheral monocytes, revealing a strong homeostatic drive for the presence of a myeloid population in the CNS (Varvel et al., PNAS 2012). This model can now be exploited to study the effect of replacing resident microglia with peripheral monocytes in animal models of AD pathology.
In addition, we have recently shown that, after brain ischemia, microglia execute neuronal death through the phagocytic uptake of stressed-but-viable neurons (Neher et al., PNAS 2013). This indicates novel therapeutic approaches for the prevention of delayed neuronal loss after stroke and possibly in neurodegenerative diseases.
Contact: Jonas Neher
Varvel NH, Grathwohl SA, Degenhardt K, Resch C, Bosch A, Jucker M, Neher JJ. Replacement of brain-resident myeloid cells does not alter cerebral β-amyloid desposition in mouse models of Alzheimer´s disease. J Ex Med 212:1803-9 (Abstract)
Brown GC, Neher JJ (2014) Microglial phagocytosis of live neurons. Nat Rev Neurosci 15:209-16 (Abstract)
Neher JJ, Emmrich JV, Fricker M, Mander PK, Théry C, Brown GC (2013) Phagocytosis executes delayed neuronal death after focal brain ischemia. Proc Natl Acad Sci USA 110:E4098-107 (Abstract)
Varvel NH, Grathwohl SA, Baumann F, Liebig C , Bosch A, Brawek B, Thal DR, Charo IF, Heppner FL, Aguzzi A, Garaschuk O, Ransohoff RM, Jucker M (2012) Microglial repopulation model reveals a robust homeostatic process for replacing CNS myeloid cells. Proc Natl Acad Sci USA 109:18150-5 (Abstract)