Erythromyeloid derived TREM2: a major determinant of Alzheimer’s disease pathology in Down syndrome.
Raha, Animesh Alexander
Stott, Simon RW
Friedland, Robert P
Journal of Alzheimer's Disease
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Raha-Chowdhury, R., Henderson, J., Raha, A. A., Stott, S. R., Vuono, R., Foscarin, S., Wilson, L., et al. (2018). Erythromyeloid derived TREM2: a major determinant of Alzheimer’s disease pathology in Down syndrome.. Journal of Alzheimer's Disease, 61 (3), 1143-1162. https://doi.org/10.3233/JAD-170814
Background: Down syndrome (DS; trisomy 21) individuals have a spectrum of hematopoietic and neuronal dysfunctions, and by the time they reach the age of 40 years, almost all develop Alzheimer’s disease (AD) neuropathology which include senile plaques and neurofibrillary tangles. Inflammation and innate immunity are key players in AD and DS. Triggering receptor expressed in myeloid cells-2 (TREM2) variants have been identified as risk factors for AD and other neurodegenerative diseases. Objective: To investigate the effects of TREM2 and the AD-associated R47H mutation on brain pathology and hematopoietic state in AD and DS. Methods: We analyzed peripheral blood, bone marrow, and brain tissue from DS, AD and age-matched control subjects by immunohistochemistry and Western blotting. TREM2-related phagocytosis was investigated using a human myeloid cell line. Results: TREM2 protein levels in brain and sera declined with age and disease progression in DS. We observed soluble TREM2 in the brain parenchyma that may be carried by a subset of microglia, macrophages or exosomes. Two DS cases had the AD-associated TREM2-R47H mutation, which manifested a morphologically extreme phenotype of megakaryocytes and erythrocytes in addition to impaired trafficking of TREM2 to the erythroid membrane. TREM2 was shown to be involved in phagocytosis of red blood cells. TREM2 was seen in early and late endosomes. Silencing TREM2 using siRNA in THP1 cells resulted in significant cell death. Conclusion: We provide evidence that peripheral TREM2 originating from erythromyeloid cells significantly determines AD neuropathology in DS subjects. Understanding the molecular signaling pathways mediated by TREM2 may reveal novel therapeutic targets.
Alzheimer’s disease, dementia, Down syndrome, innate immunity, immunomodulation, inflammation, myelination, myeloid hypothesis, neurodegeneration, soluble TREM2
This research was funded by Medical Research Council (MRC grant number RNAG/254), National Institute of Health Research (NIHR), the Down’s Syndrome Association, The John Van Geest Foundation and Cambridgeshire and Peterborough Foundation NHS Trust, Cambridge, UK.
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External DOI: https://doi.org/10.3233/JAD-170814
This record's URL: https://www.repository.cam.ac.uk/handle/1810/271360
Attribution 4.0 International
Licence URL: http://creativecommons.org/licenses/by/4.0/