BEGIN:VCALENDAR VERSION:2.0 PRODID:-//Talks.cam//talks.cam.ac.uk// X-WR-CALNAME:Talks.cam BEGIN:VEVENT SUMMARY:Microglial function and dysfunction of TREM2 and ABI3\, two major risk factors for late onset Alzheimer’s disease - Christian Haass\, Germ an Center for Neurodegenerative Diseases (DZNE) Munich DTSTART:20220110T160000Z DTEND:20220110T170000Z UID:TALK167177@talks.cam.ac.uk CONTACT:47293 DESCRIPTION:Genome wide association studies have identified a number of ri sk factors for late onset Alzheimer’s disease (LOAD) in genes expressed in microglia\, among them the Triggering receptor expressed on myeloid cel ls 2 (TREM2) and Abl interactor family member 3 (ABI3). \nTREM2 is essent ial for the transition of homeostatic microglia to disease associated micr oglia. TREM2 loss of function locks microglia in a homeostatic state\, an d affects a multitude of microglia functions such as chemotaxis\, phagocyt osis\, cell survival\, lipid- and energy metabolism. Our most recent longi tudinal biomarker studies in DIAN revealed that higher TREM2 levels during the pre-clinical phase may protect humans from cognitive decline and brai n shrinkage. Thus increasing TREM2 activity may be a new therapeutic optio n for AD. We developed TREM2 modulating strategies by generating antibodie s\, which boost TREM2 protective functions. Our findings demonstrate that antibodies elevating full-length TREM2 on the cell surface allow selectiv e modulation of TREM2 dependent functions in microglia and macrophages\, w hich may be of potential therapeutic benefit in a variety of disorders whe re TREM2 plays a protective role. \nSince antibody mediated microglial ove ractivation is a concern for the application of such antibodies\, we inves tgated the protective/detrimental function of hyperactivated microglia in models for GRN deficiency. Surprisingly\, we found that inhibition of hyp eractivation by reducing TREM2 signaling even further increased neurodegen eration in GRN knockout mice. Thus even hyperactivated microglia retain a t least some protective activity. Moreover\, these findings also demonstr ated that microglial activation is reversible\, further supporting the hig hly dynamic nature of microglia. \nABI3 is involved in the coordinated re modeling of the actin cytoskeleton via F-actin nucleation\, which is a maj or regulator of cell shape\, cytokinesis\, membrane internalization\, and chemotaxis. To generate a model that closely mimics the ABI3 mutations fo und in LOAD\, we introduced the heterozygous mutation into the correspondi ng position within the mouse genome (S212F) and crossed these animals to a mouse model of amyloidogenesis. In patient derived microglia as well as microglia from our mouse model\, mutant ABI3 fails to undergo phosphoryla tion at and around the site of the serine to phenylalanine exchange. Cons istent with a central role of ABI3 in F-actin nucleation\, failure of pho sphorylation alters microglial morphology by reducing their volume and bra nch points. I will demonstrate an unexpected dysequilibrium between microg lia mediated plaque compaction and vascular\, Abeta mediated damage in ABI mutant heterozygous mice.\n\nFurther reading:\nSchlepckow K\, Monroe KM\, Kleinberger G\, Cantuti-Castelvetri L\, Parhizkar S\, Xia D\, Willem M\, Werner G\, Pettkus N\, Brunner B\, Sülzen A\, Nuscher B\, Hampel H\, Xian g X\, Feederle R\, Tahirovic S\, Park JI\, Prorok R\, Mahon C\, Liang CC\, Shi J\, Kim DJ\, Sabelström H\, Huang F\, Di Paolo G\, Simons M\, Lewcoc k JW\, Haass C (2020) Enhancing Protective Microglial Activities With a Du al Function TREM2 Antibody to the Stalk Region. EMBO Mol Med\, 12(4): e112 27.\n\nParhizkar S\, Arzberger T\, Brendel M\, Kleinberger G\, Deussing M\ , Focke C\, Nuscher B\, Xiong M\, Ghasemigharagoz A\, Katzmarski N\, Krase mann S\, Lichtenthaler SF\, Müller SA\, Colombo A\, Monasor LS\, Tahirovi c S\, Herms J\, Willem M\, Pettkus N\, Butovsky O\, Bartenstein P\, Edbaue r D\, Rominger A\, Ertürk A\, Grathwohl SA\, Neher JJ\, Holtzman DM\, Mey er-Luehmann M\, Haass C (2019) Loss of TREM2 function increases amyloid se eding but reduces plaque-associated ApoE. Nature Neuroscience 22(2): 191-2 04.\n\nSuárez-Calvet M\, Caballero MA\, Kleinberger G\, Bateman RJ\, Faga n AM\, Morris JC\, Levin J\, Danek A\, Ewers M\, Haass C for the Dominantl y Inherited Alzheimer Network (2016) Early changes of CSF sTREM2 in Domina ntly Inherited Alzheimer’s Disease follow markers of Amyloid Deposition and Neuronal Injury. Science Translational Medicine 8(369): 369ra178. \n\n Kleinberger G.\, Yamanishi Y.\, Suárez-Calvet M.\, Czirr E.\, Lohmann E.\ , Cuyvers E.\, Struyfs H.\, Pettkus N.\, Wenninger-Weinzierl A.\, Mazaheri F.\, Tahirovic S.\, Lleó A.\, Alcolea D.\, Fortea J.\, Willem M.\, Lammi ch S.\, Molinuevo J. L.\, Sanchez-Valle R.\, Antonell A.\, Ramirez A.\, He neka M.\, Sleegers K.\, van der Zee J.\, Martin J.-J.\, Engelborghs S.\, D emirtas-Tatlidede A.\, Zetterberg H.\, Van Broeckhoven C.\, Gurvit H.\, Wy ss-Coray T.\, Hardy J.\, Colonna M. & Haass C. (2014) TREM2 mutations lin ked to neurodegeneration impair cell surface transport and phagocytosis. Science Translational Medicine\, 6\, 1-29.\n\nReview article:\nLewcock JW\ , Schlepckow K\, Di Paolo G\, Tahirovic S\, Monroe KM\, Haass C (2020) Eme rging Microglia Biology Defines Novel Therapeutic Approaches for Alzheimer ’s Disease. Neuron \nhttps://doi.org/10.1016/j.neuron.2020.09.029\n LOCATION:https://zoom.us/j/99122826836?pwd=NEpzRHBFNzAwUGhzOGp6TDBoMzJUUT0 9 END:VEVENT END:VCALENDAR