Biologic TNF-\u03b1 inhibitors reduce microgliosis, neuronal loss, and tau phosphorylation in a transgenic mouse model of tauopathy

Weijun Ou,Rudy Chang,Matthew Choi,Jiahong Sun,Demi M Castellanos,David H Cribbs,Juste Simanauskaite,Rachita K Sumbria,Joshua Yang,Nataraj Jagadeesan,Karen D Parfitt

doi:10.1186/s12974-021-02332-7

Abstract

BackgroundTumor 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.MethodsSix-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.ResultsEtanercept 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.ConclusionBoth TfRMAb-TNFR (BBB-penetrating) and non-BBB-penetrating (etanercept) biologic TNFIs showed therapeutic effects in the PS19 mouse model of tauopathy.

Highlights

Alzheimer’s disease (AD) is a progressive neurodegenerative disease that was first discovered in 1906 by the German clinical psychiatrist and neuroanatomist, Aloïs Alzheimer [1]
Effect of biologic TNF‐α inhibitors on pTau (Ser202, Thr205) in the PS19 mice To determine the impact of Tumor necrosis factor-α (TNF-α) inhibitors on tau pathology, we quantified the pTau-positive area in the cortex, hippocampus, entorhinal cortex, and amygdala using the AT8 antibody
While TfRMAb-TNF-α receptor (TNFR) resulted in a 61% decrease (p < 0.05) in the overall AT8-positive area in the female PS19 mice (Fig. 1C–D; Additional file 3: Fig. S2A), surprisingly there was no change in the AT8-positive area in the TfRMAb-TNFR-treated male PS19 mice compared to the PS19-Saline mice (Fig. 1B, D; Additional file 3: Fig. S2A)

Summary

Introduction

Alzheimer’s disease (AD) is a progressive neurodegenerative disease that was first discovered in 1906 by the German clinical psychiatrist and neuroanatomist, Aloïs Alzheimer [1]. Among the pro-inflammatory mediators, TNF-α is one of the main inflammatory cytokines involved in initiating and propagating an inflammatory response [7]. Both clinical and preclinical studies support the role of peripheral and central nervous system (CNS) TNF-α in AD, and elevated TNF-α levels were observed in the serum [8, 9] and postmortem brains of AD patients and AD mouse models [10, 11]. 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 present study aimed to investigate the effects of TfRMAb-TNFR (BBBpenetrating TNFI) and etanercept (non-BBB-penetrating TNFI) in the PS19 transgenic mouse model of tauopathy

Methods

Results

Discussion

Conclusion