The effect of amyloid on microglia-neuron interactions before plaque onset occurs independently of TREM2 in a mouse model of Alzheimer's disease
Authors: Taylor R Jay
Gary E Landreth
Victoria E von Saucken
Journal: Neurobiology of Disease (2020)
Discipline: NEUROSCIENCE & BEHAVIOR
Keywords: Amyloid accumulation; Neurites; Phagocytosis; Pre-plaque; Triggering receptor expressed on myeloid cells 2.
Affiliations: Stark Neurosciences Research Institute, Indiana University School of Medicine, Indianapolis, IN 46202, USA; Department of Neurosciences, Case Western Reserve University, Cleveland, OH 44106, USA., Department of Neurosciences, Case Western Reserve University, Cleveland, OH 44106, USA., Stark Neurosciences Research Institute, Indiana University School of Medicine, Indianapolis, IN 46202, USA; Department of Neurosciences, Case Western Reserve University, Cleveland, OH 44106, USA. Electronic address: .

Abstract:  Genetic studies identified mutations in several immune-related genes that confer increased risk for developing Alzheimer's disease (AD), suggesting a key role for microglia in AD pathology. Microglia are recruited to and actively modulate the local toxicity of amyloid plaques in models of AD through these cells' transcriptional and functional reprogramming to a disease-associated phenotype. However, it remains unknown whether microglia actively respond to amyloid accumulation before plaque deposition in AD. We compared microglial interactions with neurons that exhibit amyloid accumulation to those that do not in 1-month-old 5XFAD mice to determine which aspects of microglial morphology and function are altered by early 6E10+ amyloid accumulation. We provide evidence of preferential microglial process engagement of amyloid laden neurons. Microglia, on exposure to amyloid, also increase their internalization of neurites even before plaque onset. Unexpectedly, we found that triggering receptor expressed on myeloid cells 2 (TREM2), which is critical for microglial responses to amyloid plaque pathology later in disease, is not required for enhanced microglial interactions with neurons or neurite internalization early in disease. However, TREM2 was still required for early morphological changes exhibited by microglia. These data demonstrate that microglia sense and respond to amyloid accumulation before plaques form using a distinct mechanism from the TREM2-dependent pathway required later in disease. 

Retracted: No

PubPeer comments:
 From the  Materials and methods section,  To generate 5XFAD; Trem2u2212 u2212 mice, we crossed 5XFAD mice to Trem2u2212 u2212 mice (TREM2tm1(KOMP)Vlcg), which substitutes a lacZ reporter for exons 2, 3 and a part of exon 4 of Trem2 ( Jay et al., 2015 ). This mouse model has previously been shown to also exhibit specific misregulation of the neighboring gene Treml1 ( Kang et al., 2018 ) , though studies so far have found that this model largely recapitulates other TREM2 KO models in studies of AD ( Cheng-Hathaway et al., 2018 ; Jay et al., 2017a ). Although the authors stated as if  other Trem2 KO models recapitulated the phenotypes observed with Trem2u2212 u2212 mice from (KOMP)Vlcg, two papers cited (Cheng-Hathaway et al., 2018 ; Jay et al., 2017a ) are actually papers the same authors published previously using the  same Trem2- - mouse mode that had artifact of Treml1 misregulation. If any paper reported a direct comparison between multiple Trem2 KO models, such papers should have been cited. ,