Objective Currently no effective disease modifying agents exist for the treatment of AD. The Fyn tyrosine kinase is implicated in Alzheimer’s disease (AD) pathology triggered by amyloid-β oligomers (Aβo) and propagated by Tau. Thus, Fyn inhibition may prevent or delay disease progression. Here, we sought to repurpose the Src family kinase inhibitor oncology compound, AZD0530, for AD. Methods The pharmacokinetics and distribution of AZD0530 were evaluated in mice. Inhibition of Aβo signaling to Fyn, Pyk2 and Glu receptors by AZD0530 was tested by brain slice assays. After AZD0530 or vehicle treatment of wild type and AD transgenic mice, memory was assessed by Morris water maze and novel object recognition. For these cohorts, APP metabolism, synaptic markers (SV2 and PSD-95), and targets of Fyn (Pyk2 and Tau) were studied by immunohistochemistry and by immunoblotting. Results AZD0530 potently inhibits Fyn and prevents both Aβo-induced Fyn signaling and downstream phosphorylation of the AD risk gene product, Pyk2, and of NR2B Glu receptors in brain slices. After 4 weeks of treatment, AZD0530 dosing of APP/PS1 transgenic mice fully rescues spatial memory deficits and synaptic depletion, without altering APP or Aβ metabolism. AZD0530 treatment also reduces microglial activation in APP/PS1 mice, and rescues Tau phosphorylation and deposition abnormalities in APP/PS1/Tau transgenic mice. There is no evidence of AZD0530 chronic toxicity. Interpretation Targeting Fyn can reverse memory deficits found in AD mouse models, and rescue synapse density loss characteristic of the disease. Thus, AZD0530 is a promising candidate to test as a potential therapy for AD.
What are the novel findings of this work? Preterm delivery occurred in a higher proportion of women with SARS-CoV-2 infection in the PAN-COVID and AAP-SONPM registries compared to contemporaneous and historical national data from uninfected women in the UK and USA. The majority of preterm deliveries occurred between 32 + 0 and 36 + 6 weeks' gestation. SARS-CoV-2 infection in pregnancy did not appear to be associated with a clinically significant effect on fetal growth, adverse neonatal outcome or the rate of stillbirth. Although maternal death was uncommon, the rate was higher than expected based on UK and USA population data, which is likely explained by underascertainment of women affected by milder or asymptomatic infection in pregnancy in the PAN-COVID study, although not in the AAP-SONPM study. What are the clinical implications of this work? Pregnant women should be counseled that SARS-CoV-2 infection increases the risk of preterm delivery but not stillbirth, early neonatal death or a small baby. Healthcare providers should recommend SARS-CoV-2 vaccination in pregnant women and women planning pregnancy, alongside enhanced social distancing.
Summary Interactions in the tumour microenvironment can promote chronic lymphocytic leukaemia (CLL) cell survival, proliferation and drug resistance. A detailed comparison of three co‐culture systems designed to mimic the CLL lymph node and vascular microenvironments were performed; two were mouse fibroblast cell lines transfected with human CD40LG or CD31 and the third was a human microvascular endothelial cell line, HMEC‐1. All three co‐culture systems markedly enhanced CLL cell survival and induced a consistent change in CLL cell phenotype, characterized by increased expression of CD38, CD69, CD44 and ITGA4 (CD49d); this phenotype was absent following co‐culture on untransfected mouse fibroblasts. In contrast to HMEC‐1 cells, the CD40LG and CD31‐expressing fibroblasts also induced ZAP70 expression and marked CLL cell proliferation as evidenced by carboxyfluorescein succinimidyl ester labelling and increased Ki‐67 expression. Taken together, our data show that co‐culture on different stroma induced a remarkably similar activation phenotype in CLL cells but only the CD40LG and CD31‐expressing fibroblasts increased ZAP70 expression and CLL cell proliferation, indicating that ZAP70 may play a critical role in this process. This comparative study reveals a number of striking similarities between the co‐culture systems tested but also highlights important differences that should be considered when selecting which system to use for in‐vitro investigations.
Haploinsufficiency of the progranulin (PGRN)-encoding gene (GRN) causes frontotemporal lobar degeneration (GRN-FTLD) and results in microglial hyperactivation, TREM2 activation, lysosomal dysfunction, and TDP-43 deposition. To understand the contribution of microglial hyperactivation to pathology, we used genetic and pharmacological approaches to suppress TREM2-dependent transition of microglia from a homeostatic to a disease-associated state. Trem2 deficiency in Grn KO mice reduced microglia hyperactivation. To explore antibody-mediated pharmacological modulation of TREM2-dependent microglial states, we identified antagonistic TREM2 antibodies. Treatment of macrophages from GRN-FTLD patients with these antibodies led to reduced TREM2 signaling due to its enhanced shedding. Furthermore, TREM2 antibody-treated PGRN-deficient microglia derived from humaninduced pluripotent stem cells showed reduced microglial hyperactivation, TREM2 signaling, and phagocytic activity, but lysosomal dysfunction was not rescued. Similarly, lysosomal dysfunction, lipid dysregulation, and glucose hypometabolism of Grn KO mice were not rescued by TREM2 ablation. Synaptic loss and neurofilament light-chain (NfL) levels, a biomarker for neurodegeneration, were further elevated in the Grn/Trem2 KO cerebrospinal fluid (CSF). These findings suggest that TREM2-dependent microglia hyperactivation in models of GRN deficiency does not promote neurotoxicity, but rather neuroprotection.
Biochemical and genetic evidence implicate soluble oligomeric amyloid-β (Aβo) in triggering Alzheimer's disease (AD) pathophysiology. Moreover, constitutive deletion of the Aβo-binding cellular prion protein (PrP) prevents development of memory deficits in APP/PS1ΔE9 mice, a model of familial AD. Here, we define the role of PrP to rescue or halt established AD endophenotypes in a therapeutic disease-modifying time window after symptom onset. Deletion of at either 12 or 16 months of age fully reverses hippocampal synapse loss and completely rescues preexisting behavioral deficits by 17 months. In contrast, but consistent with a neuronal function for Aβo/PrP signaling, plaque density, microgliosis, and astrocytosis are not altered. Degeneration of catecholaminergic neurons remains unchanged by PrP reduction after disease onset. These results define the potential of targeting PrP as a disease-modifying therapy for certain AD-related phenotypes after disease onset. The study presented here further elucidates our understanding of the soluble oligomeric amyloid-β-Aβo-binding cellular prion protein (PrP) signaling pathway in a familial form of Alzheimer's disease (AD) by implicating PrP as a potential therapeutic target for AD. In particular, genetic deletion of rescued several familial AD (FAD)-associated phenotypes after disease onset in a mouse model of FAD. This study underscores the therapeutic potential of PrP deletion given that patients already present symptoms at the time of diagnosis.
Direct activation of tumor infiltrating antigen-presenting cells (APCs) by intratumoral injection of STING agonists (STINGa) leads to regression of the treated lymphoma tumor. Because STING activation induces apoptosis in lymphoma cells in vitro, we distinguished between the direct therapeutic vs the indirect immunotherapeutic properties of STINGa in vivo. Employing wild-type or STING knockout hosts bearing either wild-type or STING knockout tumor cells, we demonstrated that local tumor regression is totally dependent on STING expression by the host and is therefore immune mediated. However, distant untreated tumors are weakly affected after injection of STINGa to a single tumor site. Therefore, using the STINGa currently being tested in clinical trials, we screened for immunomodulatory agents that could synergize with the STING pathway to induce a systemic antitumor immune response and regression of distant tumors. We combined the STINGa with agents that improve APC or T-cell function. We found that modulation of both APCs and T cells can enhance control of distant lymphoma tumors by STINGa. In particular, adding an anti-GITR antibody induced lymphocyte expansion in the lymph node draining the treated site followed by increased T-cell infiltration in the distant tumor. Furthermore, more of these CD8 T cells at the distant site expressed PD-1. Therefore, blockade of PD-1 further enhanced tumor control at the distant site, leading to cure in 50% of the mice. These preclinical data provide the rationale for testing local injection of STINGa followed by agonistic anti-GITR and anti-PD-1 antibodies as immunotherapy for human lymphoma.
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