Microglia TREM2(R47H) Alzheimer-linked variant enhances excitatory transmission and reduces LTP via increased TNF-α levels

To study the mechanisms by which the p.R47H variant of the microglia gene and Alzheimer’s disease (AD) risk factor TREM2 increases dementia risk, we created Trem2(R47H) KI rats. Trem2(R47H) rats were engineered to produce human Aβ to define human-Aβ-dependent and -independent pathogenic mechanisms triggered by this variant. Interestingly, pre- and peri-adolescent Trem2(R47H) rats present increased brain concentrations of TNF-α, augmented glutamatergic transmission, suppression of Long-term-Potentiation (LTP), an electrophysiological surrogate of learning and memory, but normal Aβ levels. Acute reduction of TNF-α activity with a neutralizing anti-TNF-α antibody occludes the boost in amplitude of glutamatergic transmission and LTP suppression observed in young Trem2(R47H/R47H) rats. Thus, the microglia-specific pathogenic Trem2 variant boosts glutamatergic neuronal transmission and suppresses LTP by increasing brain TNF-α concentrations, directly linking microglia to neuronal dysfunction. Future studies will determine whether this phenomenon represents an early, Aβ-independent pathway that facilitates dementia pathogenesis in humans.