Onset of motor deficits, but not their severity, is augmented by TREM2 reduction in P301S tau transgenic mice

Abstract

AbstractBackgroundAlzheimer’s disease (AD) is characterised by extracellular amyloid‐β plaques and intracellular neurofibrillary tangles composed of the hyperphosphorylated microtubule associated protein tau. These two pathological hallmarks have been explored for decades however it remains not fully understood how they interact with each other and how they trigger disease onset and progression. Recently, in genome wide association studies other genetic risk factors have been identified. One of them being polymorphisms of the triggering receptor expressed on myeloid cells 2 (TREM2). The effects of TREM2 on disease and especially in the context of tau pathology remain poorly understood and the current literature is conflicting.MethodsHere, we have examined the effect of TREM2 on tau pathology in an P301S tau transgenic mouse model, TAU58/2. TAU58/2 mice are characterised by an early onset and progressive NFT pathology and behavioural, motor and memory deficits. TREM2 knockout (KO) mice were crossed with TAU58/2 transgenic mice and subjected to a variety of functional tests including RotaRod, elevated plus maze, open field and Morris water maze at different age time points. After behavioural assessment brains were collected and histological analysis performed.ResultsAt 2 months of age TAU58/2 mice present with moderate motor deficits on the RotaRod, this phenotype was significantly aggravated upon TREM2 reduction and complete depletion. Further, we found that TREM2 KO induces a disinhibition like phenotype in older TAU58/2 non transgenic animals. Histological analysis revealed an increase in cells positive for tau phosphorylated at serine 422, a late stage pathology marker. Interestingly, knock out of TREM2 impacted on performance of transgenic and non‐transgenic mice differently.ConclusionTaken together, our results show that reducing TREM2 exacerbates the functional deficits of TAU58/2 transgenic mice. Furthermore, we found an accelerated progression of tau phosphorylation. Hence, our work suggests that reduction and loss of TREM2 function could contribute to functional deficits in AD via augmenting tau pathology.