Artikel
Trem2 deficiency alters Alzheimer’s disease-like pathology in mice
Suche in Medline nach
Autoren
-
Kelly Miller
- Charité Universitätsmedizin Berlin, Institute of Neuropathology, Berlin, Germany
-
Pascale Eede
- Charité Universitätsmedizin Berlin, Institute of Neuropathology, Berlin, Germany
-
K. Peter Nilsson
- Charité Universitätsmedizin Berlin, Institute of Neuropathology, Berlin, Germany; Linköping University, Departments of Physics, Chemistry and Biology (IFM), Linköping, Sweden
-
Frank Heppner
- Charité Universitätsmedizin Berlin, Institute of Neuropathology, Berlin, Germany; Cluster of Excellence “NeuroCure”, Berlin, Germany; Berlin Institute of Health (BIH), Berlin, Germany
| Veröffentlicht: | 14. September 2016 |
|---|
Gliederung
Text
Introduction: Genome-wide association studies have recently identified variations in more than 20 loci that contribute to the risk of developing sporadic Alzheimer’s disease (AD), including a novel variant in the gene encoding the triggering receptor expressed on myeloid cells 2 (Trem2), which triples the risk of AD. Trem2 is expressed on myeloid cells including microglia in the brain and has previously been shown to be involved in regulating microglial phagocytosis and survival as well as engaging these cells with amyloid beta (Aβ) plaques through lipid sensing. Animal studies aimed at exploring the effects of Trem2 deficiency on AD-related neuropathology have yielded inconsistent data.
Objectives: To shed light on the pathogenetic role of Trem2 in AD, we crossed Trem2 deficient mice to APPPS1 mice modeling AD and evaluated AD-like pathology at 120 and 250 days of age.
Materials and Methods: Brains of Trem2 deficient APPPS1 mice at the age of 120d and 250d were analysed histologically as well as biochemically for Aβ plaque burden. Microglial phenotype and plaque conformation were also assessed.
Results: Our data suggest that a deletion of Trem2 in progressive stages of AD-like pathology (120d) leads to a reduction in diffuse cortical Aβ plaques resulting in altered plaque conformation. At this relatively early time-point, the total number of microglia was reduced in Trem2 deficient APPPS1 mice compared to controls, although there was no reduction in microglial plaque association. Conversely, cortical diffuse and core Aβ plaque burden was increased upon Trem2 deletion during late stages of AD-like pathology (250d) and this phenotype was accompanied by a qualitatively reduced level of microglia activation and peri-plaque localization.
Conclusion: Our analyses show that Trem2 deficiency in this AD-like mouse model led to significant alterations in pathology, thus providing important insights into the impact of Trem2 on microglia function in AD and the role of microglia in AD pathogenesis in general.
