TNF-α–mediated reduction in inhibitory neurotransmission precedes sporadic Alzheimer’s disease pathology in young Trem2 rats

Ren, Siqiang; Breuillaud, Lionel; Yao, Wen; Yin, Tao; Norris, Kelly A.; Zehntner, Simone P.; D’Adamio, Luciano

doi:10.1074/jbc.ra120.016395

Cited by 47Alzheimer's disease research and treatmentsNeuroinflammation and Neurodegeneration MechanismsNeuroscience and Neuropharmacology Research

TNF-α–mediated reduction in inhibitory neurotransmission precedes sporadic Alzheimer’s disease pathology in young Trem2 rats

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Ren, Siqiang, Breuillaud, Lionel, Yao, Wen, Yin, Tao, Norris, Kelly A., Zehntner, Simone P., D’Adamio, Luciano·2021·Journal of Biological Chemistry

DOI 10.1074/jbc.ra120.016395PMC PMC7949092

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Abstract

Alzheimer's disease (AD) is a neurodegenerative dementia associated with deposition of amyloid plaques and neurofibrillary tangles, formed by amyloid β (Aβ) peptides and phosphor-tau, respectively, in the central nervous system. Approximately 2% of AD cases are due to familial AD (FAD); ∼98% of cases are sporadic AD (SAD). Animal models with FAD are commonly used to study SAD pathogenesis. Because mechanisms leading to FAD and SAD may be distinct, to study SAD pathogenesis, we generated Trem2 R47H knock-in rats, which carry the SAD risk factor p.R47H variant of the microglia gene triggering receptor expressed on myeloid cells 2 ( TREM2 ). Trem2 R47H rats produce human-Aβ from a humanized- App rat allele because human-Aβ is more toxic than rodent-Aβ and the pathogenic role of the p.R47H TREM2 variant has been linked to human-Aβ–clearing deficits. Using periadolescent Trem2 R47H rats, we previously demonstrated that supraphysiological tumor necrosis factor-α (TNF-α) boosts glutamatergic transmission, which is excitatory, and suppresses long-term potentiation, a surrogate of learning and memory. Here, we tested the effect of the p.R47H variant on the inhibitory neurotransmitter γ-aminobutyric acid. We report that GABAergic transmission is decreased in Trem2 R47H/R47H rats. This decrease is due to acute and reversible action of TNF-α and is not associated with increased human-Aβ levels and AD pathology. Thus, the p.R47H variant changes the excitatory/inhibitory balance, favoring excitation. This imbalance could potentiate glutamate excitotoxicity and contribute to neuronal dysfunction, enhanced neuronal death, and neurodegeneration. Future studies will determine whether this imbalance represents an early, Aβ-independent pathway leading to dementia and may reveal the AD-modifying therapeutic potential of TNF-α inhibition in the central nervous system.

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The Apph allele enables the physiological production of human Aβ instead of rodent Aβ from the endogenous rat App gene.
“The Apph allele enables the physiological production of human Aβ instead of rodent Aβ from the endogenous rat App gene [43–49].”
From Analysis of early effects of human APOE isoforms on Alzheimer’s disease and type III hyperlipoproteinemia pathways using knock-in rat models with humanized APP and APOE (2024) · cites this paper as [48]
The Abstract (page unavailable) says the rats carry two humanized rat App alleles that drive production of human Aβ, supporting the claim’s central point. It does not establish that production is physiological or explicitly state that rodent Aβ is replaced. (LLM, conf=0.82)
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TNFα reduces inhibitory transmission in young Trem2 R47H Sporadic Alzheimer rats before observable Aβ and brain pathologyPreprint
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Authors: Ren, S., Breuillaud, L., Yao, W., Yin, T., Norris, K. A., Zehntner, S. P., & D’Adamio, L.
Affiliations: Rutgers, The State University of New Jersey (US)
ORCID: Ren, Siqiang
Breuillaud, Lionel
Yao, Wen
Yin, Tao
Venue: Journal of Biological Chemistry
Publisher: Elsevier BV
Published: 2021-01
Volume: 296
Pages: 100089
ISSN: 0021-9258 (ISSN-L)
DOI: 10.1074/jbc.ra120.016395
PMC: PMC7949092
OpenAlex: W3103396319
Cited by: 47
References: 61
Citations by year: 2026: 7 · 2025: 12 · 2024: 8 · 2023: 4 · 2022: 11 · 2021: 5
FWCI: 3.01
Type: journal article
Language: en
Open access: hybrid
doi.org
Licence: cc-by
www.elsevier.com/tdm/userlicense/1.0/ (tdm)
creativecommons.org/licenses/by/4.0/ (vor)
Locations: Journal of Biological Chemistry (publishedVersion, cc-by)
PubMed Central (publishedVersion, cc-by)
PubMed (publishedVersion)
Funders: National Institutes of Health
Topics: Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
Keywords: Alzheimer's disease, sporadic Alzheimer's disease, TNF-α, GABAergic neurotransmission, inhibitory neurotransmission, excitation-inhibition balance, glutamatergic neurotransmission, long-term potentiation, amyloid-beta, microglia, glutamate excitotoxicity, neurodegeneration, anti-TNF therapy
MeSH terms: Alzheimer Disease, Animals, Female, gamma-Aminobutyric Acid, Male, Membrane Glycoproteins, Receptors, Immunologic, Risk Factors, Tumor Necrosis Factor-alpha, Amyloid beta-Peptides, Neurodegenerative Diseases, Rats, GABAergic Neurons

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TNF-α–mediated reduction in inhibitory neurotransmission precedes sporadic Alzheimer’s disease pathology in young Trem2 rats

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