Biologic TNF-α Inhibitors Reduce Microgliosis, Neuronal Loss, and Tau Phosphorylation in a Transgenic Mouse Model of Tauopathy

Background Tumor necrosis factor-α (TNF-α) plays a central role in Alzheimer’s disease (AD) pathology, making biologic TNF-α inhibitors (TNFIs), including etanercept, viable therapeutics for AD. The protective effects of biologic TNFIs on AD hallmark pathology (Aβ deposition and tau pathology) have been demonstrated. However, the effects of biologic TNFIs on Aβ-independent tau pathology have not been reported. Existing biologic TNFIs do not cross the blood–brain barrier (BBB), therefore we engineered a BBB-penetrating biologic TNFI by fusing the extracellular domain of the type-II human TNF-α receptor (TNFR) to a transferrin receptor antibody (TfRMAb) that ferries the TNFR into the brain via receptor-mediated transcytosis. The present study aimed to investigate the effects of TfRMAb-TNFR (BBB-penetrating TNFI) and etanercept (non-BBB-penetrating TNFI) in the PS19 transgenic mouse model of tauopathy. Methods Six-month-old male and female PS19 mice were injected intraperitoneally with saline (n = 12), TfRMAb-TNFR (1.75 mg/kg, n = 10) or etanercept (0.875 mg/kg, equimolar dose of TNFR, n = 10) 3 days/week for 8 weeks. Age-matched littermate wild-type mice served as additional controls. Blood was collected at baseline and 8 weeks for a complete blood count. Locomotion hyperactivity was assessed by the open-field paradigm. Brains were examined for phosphorylated tau lesions (Ser202, Thr205), microgliosis, and neuronal health. The plasma pharmacokinetics were evaluated following a single intraperitoneal injection of 0.875 mg/kg etanercept or 1.75 mg/kg TfRMAb-TNFR or 1.75 mg/kg chronic TfRMAb-TNFR dosing for 4 weeks. Results Etanercept significantly reduced phosphorylated tau and microgliosis in the PS19 mouse brains of both sexes, while TfRMAb-TNFR significantly reduced these parameters in the female PS19 mice. Both TfRMAb-TNFR and etanercept treatment improved neuronal health by significantly increasing PSD95 expression and attenuating hippocampal neuron loss in the PS19 mice. The locomotion hyperactivity in the male PS19 mice was suppressed by chronic etanercept treatment. Equimolar dosing resulted in eightfold lower plasma exposure of the TfRMAb-TNFR compared with etanercept. The hematological profiles remained largely stable following chronic biologic TNFI dosing except for a significant increase in platelets with etanercept. Conclusion Both TfRMAb-TNFR (BBB-penetrating) and non-BBB-penetrating (etanercept) biologic TNFIs showed therapeutic effects in the PS19 mouse model of tauopathy

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Not AvailableAs parasitaemia is low and fluctuating during the chronic stage of infection, accurate detection of Trypanosoma evansi in blood is difficult. The primary aims of this investigation were to assess for the first time the seroprevalence of T. evansi in all agro-climatic zones of Punjab, by indirect enzyme-linked immunosorbent assay (iELISA) and card agglutination test (CATT/T. evansi), and to evaluate the risk factors associated with latent trypanosomosis. A total of 319 equine serum samples collected from 12 districts of Punjab (India) belonging to different agro-climatic zones revealed 39 (12.23%) and 9 (2.82%) samples to be positive by CATT/T. evansi and iELISA, respectively. The highest prevalence was recorded from the Ludhiana district (42.86% and 7.14% by CATT/T. evansi and iELISA, respectively) in the central plain zone (for which the overall prevalence was 15% and 4.17%, respectively). There was fair agreement between the tests for the detection of T. evansi (kappa = 0.345). Species was the most influential risk factor for infection, with odds ratios (ORs) of 2.81 and 5.63 for donkeys/ mules, in comparison with horses, by CATT/T. evansi and iELISA, respectively. The female equine population (OR = 3.13, 95% confidence interval [CI] = 1.32-7.67 [CATT]) was found to be at a higher risk of seropositivity for T. evansi, particularly on 'unorganised' (inappropriately managed) farms (OR = 3.18, 95% CI = 1.53- 6.65 [CATT]) and among animals used for commercial purposes (OR = 2.51, 95% CI = 1.20-5.21 [CATT]). In conclusion, to declare disease-free status, use of the iELISA followed by retesting of suspect samples by CATT/T. evansi is suggested.Not Availabl

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Not AvailableAs parasitaemia is low and fluctuating during the chronic stage of infection, accurate detection of Trypanosoma evansi in blood is difficult. The primary aims of this investigation were to assess for the first time the seroprevalence of T. evansi in all agro-climatic zones of Punjab, by indirect enzyme-linked immunosorbent assay (iELISA) and card agglutination test (CATT/T. evansi), and to evaluate the risk factors associated with latent trypanosomosis. A total of 319 equine serum samples collected from 12 districts of Punjab (India) belonging to different agro-climatic zones revealed 39 (12.23%) and 9 (2.82%) samples to be positive by CATT/T. evansi and iELISA, respectively. The highest prevalence was recorded from the Ludhiana district (42.86% and 7.14% by CATT/T. evansi and iELISA, respectively) in the central plain zone (for which the overall prevalence was 15% and 4.17%, respectively). There was fair agreement between the tests for the detection of T. evansi (kappa = 0.345). Species was the most influential risk factor for infection, with odds ratios (ORs) of 2.81 and 5.63 for donkeys/ mules, in comparison with horses, by CATT/T. evansi and iELISA, respectively. The female equine population (OR = 3.13, 95% confidence interval [CI] = 1.32–7.67 [CATT]) was found to be at a higher risk of seropositivity for T. evansi, particularly on ‘unorganised’ (inappropriately managed) farms (OR = 3.18, 95% CI = 1.53– 6.65 [CATT]) and among animals used for commercial purposes (OR = 2.51, 95% CI = 1.20–5.21 [CATT]). In conclusion, to declare disease-free status, use of the iELISA followed by retesting of suspect samples by CATT/T. evansi is suggested.Not Availabl

Pharmacokinetics and Brain Uptake of an IgG-TNF Decoy Receptor Fusion Protein Following Intravenous, Intraperitoneal, and Subcutaneous Administration in Mice

Tumor necrosis factor (TNF)-α is a proinflammatory cytokine active in the brain. Etanercept, the TNF decoy receptor (TNFR), does not cross the blood-brain barrier (BBB). The TNFR was re-engineered for BBB penetration as a fusion protein with a chimeric monoclonal antibody (MAb) against the mouse transferrin receptor (TfR), and this fusion protein is designated cTfRMAb-TNFR. The cTfRMAb domain of the fusion protein acts as a molecular Trojan horse and mediates transport via the endogenous BBB TfR. To support future chronic treatment of mouse models of neural disease with daily administration of the cTfRMAb-TNFR fusion protein, a series of pharmacokinetics and brain uptake studies in the mouse was performed. The cTfRMAb-TNFR fusion protein was radiolabeled and injected into mice via the intravenous, intraperitoneal (IP), or subcutaneous (SQ) routes of administration at doses ranging from 0.35 to 10 mg/kg. The distribution of the fusion protein into plasma following the IP or SQ routes was enhanced by increasing the injection dose from to 3–10 mg/kg. The fusion protein demonstrated long circulation times with high metabolic stability following the IP or SQ routes of injection. The IP or SQ routes produced concentrations of the cTfRMAb-TNFR fusion protein in brain that exceed by 20- to 50-fold the concentration of TNFα in pathologic conditions of the brain. The SQ injection is the preferred route of administration, as the level of cTfRMAb fusion protein produced in brain is comparable to that generated with intravenous injection, and at a much lower plasma area under the concentration curve of the fusion protein as compared to IP administration