Evidence map›Paper›PMID 34798897›Full record

ArticleJournal of neuroinflammation2021

CD4+ effector T cells accelerate Alzheimer's disease in mice.

Jatin Machhi, Pravin Yeapuri, Yaman Lu, Emma Foster, Rupesh Chikhale, Jonathan Herskovitz, Krista L Namminga, Katherine E Olson, Mai Mohamed Abdelmoaty, Ju Gao and 10 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 98 papers, 1 of them a synthesis that pooled it.

0numbers the graph read from it
0cells of the map it votes in
98citing papers in PubMed, 1 pooled it
10.0field-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

98 citing papers in PubMed, 1 synthesis or guideline pooled it, 148 citations in OpenAlex.

  1. Pooled it
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  17. Extracellular vesicle-based therapies for neurodegenerative diseases.NeuroImmune pharmacology and therapeutics · 2025
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38 more citing papers are in PubMed but not listed here.

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

20 authors at 5 institutions in 3 countries.

Jatin MachhiDepartment of Pharmacology and Experimental Neuroscience, University of Nebraska Medical Center, Omaha, NE, 68198, USA. jatin.machhi@unmc.edu.
Pravin YeapuriDepartment of Pharmacology and Experimental Neuroscience, University of Nebraska Medical Center, Omaha, NE, 68198, USA.
Yaman LuDepartment of Pharmacology and Experimental Neuroscience, University of Nebraska Medical Center, Omaha, NE, 68198, USA.
Emma FosterDepartment of Biological Sciences, Northern Kentucky University, Highland Heights, KY, 41099, USA.
Rupesh ChikhaleUniversity College London School of Pharmacy, Bloomsbury, London, WC1E 6DE, UK.
Jonathan HerskovitzDepartment of Pathology and Microbiology, University of Nebraska Medical Center, Omaha, NE, 68198, USA.
Krista L NammingaDepartment of Pharmacology and Experimental Neuroscience, University of Nebraska Medical Center, Omaha, NE, 68198, USA.
Katherine E OlsonDepartment of Pharmacology and Experimental Neuroscience, University of Nebraska Medical Center, Omaha, NE, 68198, USA.
Mai Mohamed AbdelmoatyDepartment of Pharmaceutical Sciences, University of Nebraska Medical Center, Omaha, NE, 68198, USA.
Ju GaoDepartment of Pharmacology and Experimental Neuroscience, University of Nebraska Medical Center, Omaha, NE, 68198, USA.
Rolen M QuadrosDepartment of Pharmacology and Experimental Neuroscience, University of Nebraska Medical Center, Omaha, NE, 68198, USA.
Tomomi KiyotaDepartment of Safety Assessment, Genentech Inc., South San Francisco, CA, 94080, USA.
Liang JingjingDepartment of Pharmacology and Experimental Neuroscience, University of Nebraska Medical Center, Omaha, NE, 68198, USA.
Bhavesh D KevadiyaDepartment of Pharmacology and Experimental Neuroscience, University of Nebraska Medical Center, Omaha, NE, 68198, USA.
Xinglong WangDepartment of Pharmacology and Experimental Neuroscience, University of Nebraska Medical Center, Omaha, NE, 68198, USA.
Yutong LiuDepartment of Pharmacology and Experimental Neuroscience, University of Nebraska Medical Center, Omaha, NE, 68198, USA.
Larisa Y PoluektovaDepartment of Pharmacology and Experimental Neuroscience, University of Nebraska Medical Center, Omaha, NE, 68198, USA.
Channabasavaiah B GurumurthyDepartment of Pharmacology and Experimental Neuroscience, University of Nebraska Medical Center, Omaha, NE, 68198, USA.
R Lee MosleyDepartment of Pharmacology and Experimental Neuroscience, University of Nebraska Medical Center, Omaha, NE, 68198, USA.
Howard E GendelmanDepartment of Pharmacology and Experimental Neuroscience, University of Nebraska Medical Center, Omaha, NE, 68198, USA. hegendel@unmc.edu.ORCID http://orcid.org/0000-0002-7831-0370
University of Nebraska Medical Center · USNational Research Centre · EGNebraska Medical Center · USNorthern Kentucky University · USUniversity College London · GB

Funding

Therapeutics Core (Page 286)P30MH062261 · NIMH · UNIVERSITY OF NEBRASKA MEDICAL CENTER · PI BUCH, SHILPA J., FOX, HOWARD S · 2000 to 2021
$37.7M
Targeted Neuro Protection of HIV-1 Associated Neurologic DiseaseP01MH064570 · NIMH · UNIVERSITY OF ROCHESTER · PI GELBARD, HARRIS A · 2001 to 2014
$19.4M
Pharmacokinetics and Drug-Drug InteractionsP01DA028555 · NIDA · UNIVERSITY OF NEBRASKA MEDICAL CENTER · PI BOSKA, MICHAEL DOUGLAS · 2010 to 2019
$16.8M
Neuroprotective Immunity and HIV DementiaR01NS034239 · NINDS · UNIVERSITY OF NEBRASKA MEDICAL CENTER · PI Howard E Gendelman, R Lee Mosley · 1995 to 2026
$12.3M
Proteomics CoreP01NS043985 · NINDS · UNIVERSITY OF NEBRASKA MEDICAL CENTER · PI BOSKA, MICHAEL DOUGLAS · 2003 to 2012
$11.8M
Role of EAAT2 and AEG-1 in Astrocyte Dysfunction and NeurodegenerationP01NS031492 · NINDS · ST. LUKE'S-ROOSEVELT INST FOR HLTH SCIS · PI FISHER, PAUL B · 1993 to 2007
$10.9M
Nanomedicine and NeuroAIDSR01NS036126 · NINDS · UNIVERSITY OF NEBRASKA MEDICAL CENTER · PI GENDELMAN, HOWARD E · 1997 to 2017
$5.7M
Targeted lipid nanoparticles for gene therapeutics delivery approach to eradicating HIV reservoirsR01MH121402 · NIMH · UNIVERSITY OF NEBRASKA MEDICAL CENTER · PI Benson Edagwa, Howard E Gendelman · 2019 to 2026
$4.9M
Immunovascular interactions in postoperative delirium superimposed on dementia (DSD).RF1AG079138 · NIA · DUKE UNIVERSITY · PI GELBARD, HARRIS A, TERRANDO, NICCOLO · 2022 to 2025
$3.6M
SMART HANDR01AG043540 · NIA · UNIVERSITY OF NEBRASKA MEDICAL CENTER · PI GENDELMAN, HOWARD E, POLUEKTOVA, LARISA Y · 2013 to 2017
$3.1M
Neuroimmunology of Disease Training ProgramT32NS105594 · NINDS · UNIVERSITY OF NEBRASKA MEDICAL CENTER · PI Aditya N Bade, Howard E Gendelman · 2018 to 2026
$1.4M
NIA NIH HHS R01 AG043540NIA NIH HHS RF1 AG079138NIDA NIH HHS P01 DA028555NIMH NIH HHS P01 MH064570NIMH NIH HHS P01 MH64570NIMH NIH HHS P30 MH062261NIMH NIH HHS R01 MH121402NINDS NIH HHS 2R01 NS034239NINDS NIH HHS P01 NS031492NINDS NIH HHS P01 NS043985NINDS NIH HHS P01 NS31492NINDS NIH HHS P01 NS43985NINDS NIH HHS R01 NS034239NINDS NIH HHS R01 NS036126NINDS NIH HHS R01 NS36126NINDS NIH HHS T32 NS105594
6 · The paper itself

Abstract

backgroundAlzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by pathological deposition of misfolded self-protein amyloid beta (Aβ) which in kind facilitates tau aggregation and neurodegeneration. Neuroinflammation is accepted as a key disease driver caused by innate microglia activation. Recently, adaptive immune alterations have been uncovered that begin early and persist throughout the disease. How these occur and whether they can be harnessed to halt disease progress is unclear. We propose that self-antigens would induct autoreactive effector T cells (Teffs) that drive pro-inflammatory and neurodestructive immunity leading to cognitive impairments. Here, we investigated the role of effector immunity and how it could affect cellular-level disease pathobiology in an AD animal model.

methodsIn this report, we developed and characterized cloned lines of amyloid beta (Aβ) reactive type 1 T helper (Th1) and type 17 Th (Th17) cells to study their role in AD pathogenesis. The cellular phenotype and antigen-specificity of Aβ-specific Th1 and Th17 clones were confirmed using flow cytometry, immunoblot staining and Aβ T cell epitope loaded haplotype-matched major histocompatibility complex II IA

resultsThe propagated Aβ-Th1 and Aβ-Th17 clones were confirmed stable and long-lived. Treatment of APP/PS1 mice with Aβ reactive Teffs accelerated memory impairment and systemic inflammation, increased amyloid burden, elevated microglia activation, and exacerbated neuroinflammation. Both Th1 and Th17 Aβ-reactive Teffs progressed AD pathology by downregulating anti-inflammatory and immunosuppressive regulatory T cells (Tregs) as recorded in the periphery and within the central nervous system.

conclusionsThese results underscore an important pathological role for CD4+ Teffs in AD progression. We posit that aberrant disease-associated effector T cell immune responses can be controlled. One solution is by Aβ reactive Tregs.

Indexed as

Alzheimer DiseaseAmyloid beta-Protein PrecursorAmyloidosisAnimalsCD4-Positive T-LymphocytesCognition DisordersInflammationMiceMice, TransgenicPresenilin-1Th17 CellsTh1 CellsT-Lymphocytes, RegulatoryAmyloid beta-Protein PrecursorAPP protein, humanPresenilin-1PSEN1 protein, humanAlzheimer’s disease (AD)Amyloid beta (Aβ)APP/PS1 transgenic miceEffector T cell (Teff)Regulatory T cell (Treg)T cell

Identifiers

PMID34798897
PMCPMC8603581
OpenAlexW3212913899

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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.