Loss of TREM2 rescues hyperactivation of microglia, but not lysosomal deficits and neurotoxicity in models of progranulin deficiency

• DOI: 10.15252/embj.2021109108
• Publication Date: 2022-01-12T11:00:24Z
• Authors: Anika Reifschneider; Sophie Robinson; Bettina van Lenge...; Johannes Gnörich; Todd Logan; Steffanie Heindl; Miriam A Vogt; Endy Weidinger; Lina Riedl; Karin Wind; Artem Zatcepin; Ida Pesämaa; Sophie Haberl; Brigitte Nuscher; Gernot Kleinberger; Julien Klimmt; Julia K Götzl; Arthur Liesz; Katharina Bürger; Matthias Brendel; Johannes Levin; Janine Diehl‐Schmid; Jung Suh; Gilbert Di Paolo; Joseph W Lewcock; Kathryn M Monroe; Dominik Paquet; Anja Capell; Christian Haass
• Keywords: TREM2; Neurotoxicity; Frontotemporal lobar degeneration

Haploinsufficiency of the progranulin (PGRN)‐encoding gene (GRN) causes frontotemporal lobar degeneration (GRN‐FTLD) and results in microglial hyperactivation, TREM2 activation, lysosomal dysfunction, TDP‐43 deposition. To understand contribution hyperactivation to pathology, we used genetic pharmacological approaches suppress TREM2‐dependent transition microglia from a homeostatic disease‐associated state. Trem2 deficiency Grn KO mice reduced hyperactivation. explore antibody‐mediated modulation states, identified antagonistic antibodies. Treatment macrophages GRN‐FTLD patients with these antibodies led signaling due its enhanced shedding. Furthermore, antibody‐treated PGRN‐deficient derived human‐induced pluripotent stem cells showed signaling, phagocytic activity, but dysfunction was not rescued. Similarly, lipid dysregulation, glucose hypometabolism were rescued by ablation. Synaptic loss neurofilament light‐chain (NfL) levels, biomarker for neurodegeneration, further elevated Grn/Trem2 cerebrospinal fluid (CSF). These findings suggest that models GRN does promote neurotoxicity, rather neuroprotection.