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

ABSTRACT: 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 Trem2R47H KI rats. Trem2R47H 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 Trem2R47H 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 Trem2R47H/R47H rats. Thus, the microg

SUBMITTER: Ren S 

PROVIDER: S-EPMC7338048 | biostudies-literature | 2020 Jun

REPOSITORIES: biostudies-literature