Evidence map›Paper›PMID 34972522›Full record

ArticleJournal of neuroinflammation2021

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

Weijun Ou, Joshua Yang, Juste Simanauskaite, Matthew Choi, Demi M Castellanos, Rudy Chang, Jiahong Sun, Nataraj Jagadeesan, Karen D Parfitt, David H Cribbs and 1 more

Open access · goldAbstract read
PubMed Full text at PMC Publisher
In one paragraph

Article in Journal of neuroinflammation, 2021. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 52 papers.

0numbers the graph read from it
0cells of the map it votes in
52citing papers in PubMed
8.9field-weighted citation impact, top 1% of its field
1 · What the graph read from it

What it found

Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.

The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.

2 · The registry

The trial behind it

Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.

Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.

3 · Its place in the literature

Who cites it

52 citing papers in PubMed, 104 citations in OpenAlex.

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4 · The record

Corrections and comments

PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.

5 · Who and what money

Authors and funding

11 authors at 5 institutions in 1 country.

Weijun OuDepartment of Biomedical and Pharmaceutical Sciences, School of Pharmacy, Chapman University, Irvine, CA, 92618, USA.
Joshua YangHenry E. Riggs School of Applied Life Sciences, Keck Graduate Institute, Claremont, CA, 91711, USA.
Juste SimanauskaiteDepartment of Neuroscience, Pomona College, Claremont, CA, 91711, USA.
Matthew ChoiKeck Science Department, Claremont McKenna College, Claremont, CA, 91711, USA.
Demi M CastellanosHenry E. Riggs School of Applied Life Sciences, Keck Graduate Institute, Claremont, CA, 91711, USA.
Rudy ChangDepartment of Biomedical and Pharmaceutical Sciences, School of Pharmacy, Chapman University, Irvine, CA, 92618, USA.
Jiahong SunDepartment of Biomedical and Pharmaceutical Sciences, School of Pharmacy, Chapman University, Irvine, CA, 92618, USA.
Nataraj JagadeesanDepartment of Biomedical and Pharmaceutical Sciences, School of Pharmacy, Chapman University, Irvine, CA, 92618, USA.
Karen D ParfittDepartment of Neuroscience, Pomona College, Claremont, CA, 91711, USA.
David H CribbsMIND Institute, University of California, Irvine, CA, 92697, USA.
Rachita K SumbriaDepartment of Biomedical and Pharmaceutical Sciences, School of Pharmacy, Chapman University, Irvine, CA, 92618, USA. sumbria@chapman.edu.ORCID http://orcid.org/0000-0002-7459-0723
Chapman University · USKeck Graduate Institute · USPomona College · USClaremont McKenna College · USUniversity of California, Irvine · US

Funding

A Brain Penetrating Bi-functional Transferrin Receptor Antibody-TNF-alpha Decoy Receptor Fusion Protein for Alzheimer's DiseaseR01AG062840 · NIA · KECK GRADUATE INST OF APPLIED LIFE SCIS · PI SUMBRIA, RACHITA · 2019 to 2024
$1.9M
NIA NIH HHS R01 AG062840NIA NIH HHS R01AG062840
6 · The paper itself

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.

Indexed as

AnimalsDisks Large Homolog 4 ProteinEtanerceptFemaleGliosisHippocampusHumansHyperkinesisMaleMiceMice, TransgenicNeuronsPhosphorylationReceptors, Tumor Necrosis FactorTauopathiestau ProteinsDisks Large Homolog 4 ProteinDlg4 protein, mouseEtanerceptMapt protein, mouseReceptors, Tumor Necrosis Factortau ProteinsTumor Necrosis Factor-alphaAlzheimer’s diseaseBiologic TNF-α inhibitorBlood–brain barrierMicrogliosisMolecular Trojan HorseTauTransferrin receptor

Identifiers

PMID34972522
PMCPMC8719395
OpenAlexW4206634938

What OpenQuestion holds

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LicenceCC BY
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Registered trials

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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.