An immune response is part of most neurological diseases, and the development of late-onset Alzheimer's Disease (AD) has been linked to mutations in immune related genes. In additon, environmental and life-style factors that induce peripheral inflammations (such as infections, diabetes or obesity) significantly increase the risk to develop AD. This indicates a significant contribution of immunity to AD pathogenesis. The immune response during AD is largely driven by the brain's resident macrophages, the microglia, which are attracted to and surround Aβ deposits in the AD brain. However, various aspects of the microglial role in AD pathogenesis remain unclear.
1. To investigate how peripheral inflammatory stimuli affect the brain's immune response, how they induce innate immune memory in the brain, and how immune memory affects neurodegenerative disease pathology and aging.
2. To understand how microglia contribute to AD pathology and in particular to amyloidosis and the resulting neuronal damage.
3. To understand microglial heterogeneity in neurodegenerative diseases and aging and delineate which microglial subtypes may play pathological roles.
To this end we use various models of peripheral inflammation and profile the microglial immune response to secondary stimuli, including pathological changes in neurodegenerative disease models (together with the Experimental Neuropathology Group). We isolate microglia from adult and aged brains and study their molecular profiles (transcriptional, epigenetic) and functions (phagocytic behavior and inflammatory responses). Together with the Molecular Imaging Unit we use multiphoton imaging to study microglial behavior in the aging brain and in APP transgenic mice.
In the Neuroimmunology group, we have recently found that microglia are capable of "remembering" inflammatory insults, i.e. microglia show adaption of their immune responses to subsequent stimuli for extended periods of time. Importantly, we found that these long-term adjustments in microglial immune responses had significant effects on brain pathology in mouse models of AD pathology and stroke. Moreover, we could demonstrate that this adaptive response is based on epigenetic reprogramming of microglial cells. Thus, our results indicate that microglia can integrate different inflammatory stimuli over long periods of time, with significant effects on brain disease (Wendeln et al., Nature, 2018). This was the first description of "innate immune memory" in the brain and may explain how inflammatory conditions in human patients (such as infections but also diabetes or obesity) can increase the risk to develop Alzheimer's Disease or can modify the progression of neurodegenerative disease pathology (Neher and Cunningham, Trends in Immunology, 2019).
In other studies, we have contributed to understanding the role of microglia in "seeding" Aβ plaques (Parhizkar et al., Nature Neurosci., 2019) and have demonstrated that invading monocytes promote inflammation after epilepsy (Varvel et al., PNAS, 2016) but are unable to affect pathology in mouse models of cerebral β-amyloidosis (Varvel et al., J. Exp. Med., 2015)
Wagner J, Degenhardt K, Veit M, Louros N, Konstantoulea K, Skodras A, Wild K, Liu P, Obermüller U, Bansal V, Dalmia A, Häsler LM, Lambert M, De Vleeschouwer M, Davies HA, Madine J, Kronenberg-Versteeg D, Feederle R, Del Turco D, Nilsson KPR, Lashley T, Deller T, Gearing M, Walker LC, Heutink P, Rousseau F, Schymkowitz J, Jucker M, Neher JJ (2022) Medin co-aggregates with vascular amyloid-β in Alzheimer's disease. Nature 612:7938 (Abstract)
Neher JJ (2021) Reversal of immune-cell shutdown protects the ageing brain. Nature 590(7844):44-45 (Abstract)
Degenhardt K, Wagner J, Skodras A,
Neher JJ, Cunningham C (2019) Priming Microglia for Innate Immune Memory in the Brain. Trends in immunology 40:358-374 (Abstract)
Parhizkar S, Arzberger T, Brendel M, Kleinberger G, Deussing M, Focke C, Nuscher B, Xiong M, Ghasemigharagoz A, Katzmarski N, Krasemann S, Lichtenthaler SF, Müller SA, Colombo A, Nonasor LS, Tahirovic S, Herms J, Willem M, Pettkus N, Butovsky O, Bartenstein P, Edbauer D, Rominger A, Ertürk A, Grathwohl SA, Neher JJ, Holtzman DM, Meyer-Luehmann M, Haass C (2019) Loss of TREM2 fuction increases amyloid seeding but reduces plaque-associated ApoE. Nature Neuroscience 22(2):191-204 (Abstract)
Wendeln AC, Degenhardt K, Kaurani L, Gertig M, Ulas T, Jain G, Wagner J, Häsler LM, Wild K, Skodras A, Blank T, Staszewski O, Datta M, Centeno TP, Capece V, Islam MR, Kerimoglu C, Staufenbiel M, Schultze JL, Beyer M, Prinz M, Jucker M, Fischer A, Neher JJ (2018) Innate immune memory in the brain shapes neurological disease hallmarks. Nature 556:332-338 (Abstract)
Varvel NU, Neher JJ, Bosch A, Wang W, Ransohoff RM, Miller RJ, Dingledine R (2016) Infiltrating monocytes promote brain inflammation and exacerbate neuronal damage after status epilepticus. Proc Natl Acad Sci USA 113(38): E5665-74
Varvel NH, Grathwohl SA, Degenhardt K, Resch C, Bosch A, Jucker M, Neher JJ (2015) Replacement of brain-resident myeloid cells does not alter cerebral β-amyloid deposition 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)
Center of Neurology
Hertie Institute for Clinical Brain Research
Department Cellular Neurology
Phone: +49 (0)7071 925-4351