TNF-α-mediated reduction in inhibitory neurotransmission precedes sporadic Alzheimer's disease pathology in young Trem2R47H rats
- PMID: 33434745
- PMCID: PMC7949092
- DOI: 10.1074/jbc.RA120.016395
TNF-α-mediated reduction in inhibitory neurotransmission precedes sporadic Alzheimer's disease pathology in young Trem2R47H rats
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 Trem2R47H knock-in rats, which carry the SAD risk factor p.R47H variant of the microglia gene triggering receptor expressed on myeloid cells 2 (TREM2). Trem2R47H 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 Trem2R47H 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 Trem2R47H/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.
Keywords: Alzheimer's disease; Aβ; GABA; TNF-α; Trem2; animal model; neurodegenerative disease; rats; synaptic plasticity.
Copyright © 2020 The Authors. Published by Elsevier Inc. All rights reserved.
Conflict of interest statement
Conflict of interest The authors declare that they have no conflicts of interest with the contents of this article.
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References
-
- Guerreiro R., Wojtas A., Bras J., Carrasquillo M., Rogaeva E., Majounie E., Cruchaga C., Sassi C., Kauwe J.S., Younkin S., Hazrati L., Collinge J., Pocock J., Lashley T., Williams J., Alzheimer Genetic Analysis, G. TREM2 variants in Alzheimer's disease. N. Engl. J. Med. 2013;368:117–127. - PMC - PubMed
-
- Zhou S.L., Tan C.C., Hou X.H., Cao X.P., Tan L., Yu J.T. TREM2 variants and neurodegenerative diseases: a systematic review and meta-analysis. J. Alzheimers Dis. 2019;68:1171–1184. - PubMed
-
- Wunderlich P., Glebov K., Kemmerling N., Tien N.T., Neumann H., Walter J. Sequential proteolytic processing of the triggering receptor expressed on myeloid cells-2 (TREM2) protein by ectodomain shedding and gamma-secretase-dependent intramembranous cleavage. J. Biol. Chem. 2013;288:33027–33036. - PMC - PubMed
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