Microglia TREM2R47H Alzheimer-linked variant enhances excitatory transmission and reduces LTP via increased TNF-α levels

• DOI: 10.7554/elife.57513
• Publication Date: 2020-06-24T12:00:14Z
• Authors: Siqiang Ren; Wen Yao; Marc D Tambini; Tao Yin; Kelly A Norris; Luciano D'Adamio
• Keywords: LTP induction

To study the mechanisms by which p.R47H variant of microglia gene and Alzheimer's disease (AD) risk factor TREM2 increases dementia risk, we created Trem2R47H KI rats. rats were engineered to produce human Aβ define human-Aβ-dependent -independent pathogenic triggered this variant. Interestingly, pre- peri-adolescent present increased brain concentrations TNF-α, augmented glutamatergic transmission, suppression Long-term-Potentiation (LTP), an electrophysiological surrogate learning memory, but normal levels. Acute reduction TNF-α activity with a neutralizing anti-TNF-α antibody occludes boost in amplitude transmission LTP observed young Trem2R47H/R47H Thus, microglia-specific Trem2 boosts neuronal suppresses increasing concentrations, directly linking dysfunction. Future studies will determine whether phenomenon represents early, Aβ-independent pathway that facilitates pathogenesis humans.