Exaggerated inflammation, impaired host defense, and neuropathology in progranulin-deficient mice

Abstract

Progranulin (PGRN) is a widely expressed protein involved in diverse biological processes. Haploinsufficiency of PGRN in the human causes tau-negative, ubiquitin-positive frontotemporal dementia (FTD). However, the mechanisms are unknown. To explore the role of PGRN in vivo, we generated PGRN-deficient mice. Macrophages from these mice released less interleukin-10 and more inflammatory cytokines than wild type (WT) when exposed to bacterial lipopolysaccharide. PGRN-deficient mice failed to clear Listeria monocytogenes infection as quickly as WT and allowed bacteria to proliferate in the brain, with correspondingly greater inflammation than in WT. PGRN-deficient macrophages and microglia were cytotoxic to hippocampal cells in vitro, and PGRN-deficient hippocampal slices were hypersusceptible to deprivation of oxygen and glucose. With age, brains of PGRN-deficient mice displayed greater activation of microglia and astrocytes than WT, and their hippocampal and thalamic neurons accumulated cytosolic phosphorylated transactivation response element DNA binding protein–43. Thus, PGRN is a key regulator of inflammation and plays critical roles in both host defense and neuronal integrity. FTD associated with PGRN insufficiency may result from many years of reduced neutrotrophic support together with cumulative damage in association with dysregulated inflammation.

Pathological correlates of white matter hyperintensities in a case of progranulin mutation associated frontotemporal dementia

“…This is consistent with the large number of activated CD68 positive microglia in GRN mouse models (Lui et al, 2016; Martens et al, 2012; Yin et al, 2009, 2010) and patients with GRN mutations, especially in frontal white matter (Lant et al, 2014; Taipa et al, 2017), which could cause white matter damage through excessive phagocytosis. We also identified many amoeboid CR3/43 positive microglia in areas of severe WMH, suggesting that microglia with antigen-presenting cell function were particularly active in these regions, which has not been described previously in FTD.…”

The Protein Zfand5 Binds and Stabilizes mRNAs with AU-rich Elements in Their 3′-Untranslated Regions

“…RAW cells were from ATCC. Bone marrow-derived macrophages were prepared as described (20). Animal studies were approved by the Institutional Animal Care and Use Committee of Weill Cornell Medical College.…”

“…RNA EMSA-Cy5-labeled RNA probe (1 pmol) was incubated with purified Zfand5, TTP, or BSA, 10 pmol of poly(U) 20 (Microsynth, Balgach, Schweiz), plus 1 l of RNase inhibitor mixture in a total volume of 10 l in a binding buffer (10 mM Tris, 50 mM KCl, 2.5 mM DTT, 0.25% Tween 20, pH 7.5) at room temperature for different times. The reaction mixtures were separated on a 5% native polyacrylamide gel as described (21) and visualized with the Odyssey Infrared Imaging System (LI-COR Biotechnology).…”

Microglial Activation in Stroke: Therapeutic Targets

“…Progranulin-deficient macrophages and microglia are cytotoxic to hippocampal cells in vitro, and progranulin-deficient hippocampal slices are hypersusceptible to deprivation of oxygen and glucose. 181 The role of Nurr1 and progranulin in postischemic inflammation has not been reported.…”