Tnf-Alpha-Mediated Reduction In Inhibitory Neurotransmission Precedes Sporadic Alzheimer'S Disease Pathology In Young Trem2(R47h) Rats

Alzheimer's disease (AD) is a neurodegenerative dementia associated with deposition of amyloid plaques and neurofibrillary tangles, formed by amyloid beta (A beta) peptides and phosphor-tau, respectively, in the central nervous system. Approximately 2% of AD cases are due to familial AD (FAD); similar to 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-A beta from a humanized-App rat allele because human-A beta is more toxic than rodent-A beta and the pathogenic role of the p.R47H TREM2 variant has been linked to human-A beta-clearing deficits. Using periadolescent Trem2(R47H) rats, we previously demonstrated that supraphysiological tumor necrosis factor-alpha (TNF-alpha) 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 gamma-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-alpha and is not associated with increased human-A beta 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, A beta-independent pathway leading to dementia and may reveal the AD-modifying therapeutic potential of TNF-alpha inhibition in the central nervous system.