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Erythromyeloid-derived TREM2: A major determinant of Alzheimer's disease pathology in down syndrome

Raha-Chowdhury, R., Henderson, J.W., Raha, A.A., Stott, S.R.W., Vuono, R., Foscarin, S., Wilson, L., Annus, T., Fincham, R., Allinson, K., and others. (2018) Erythromyeloid-derived TREM2: A major determinant of Alzheimer's disease pathology in down syndrome. Journal of Alzheimer's Disease, 61 (3). pp. 1143-1162. ISSN 1387-2877. (doi:10.3233/JAD-170814) (KAR id:79835)

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Official URL
http://dx.doi.org/10.3233/JAD-170814

Abstract

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 includes 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 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.

Item Type: Article
DOI/Identification number: 10.3233/JAD-170814
Uncontrolled keywords: small interfering RNA; triggering receptor expressed on myeloid cells 2; immunoglobulin receptor; membrane protein; TREM2 protein, human, adult; age; aged; Alzheimer disease; Article; bone marrow culture; brain tissue; cell death; cell membrane; clinical article; controlled study; disease course; Down syndrome; endosome; erythrocyte; erythroid cell; exosome; female; gene mutation; gene silencing; hematopoiesis; human; human cell; human tissue; immunohistochemistry; macrophage; male; megakaryocyte; microglia; middle aged; parenchyma; phagocytosis; priority journal; protein function; protein transport; THP-1 cell line; Western blotting; Alzheimer disease; brain; cell line; complication; disease exacerbation; Down syndrome; genetics; innate immunity; metabolism; pathology; single nucleotide polymorphism; very elderly, Aged; Aged, 80 and over; Alzheimer Disease; Brain; Cell Line; Disease Progression; Down Syndrome; Exosomes; Female; Humans; Immunity, Innate; Macrophages; Male; Membrane Glycoproteins; Microglia; Middle Aged; Phagocytosis; Polymorphism, Single Nucleotide; Receptors, Immunologic
Divisions: Divisions > Division of Natural Sciences > Medway School of Pharmacy
Depositing User: Romina Vuono
Date Deposited: 29 Jan 2020 10:26 UTC
Last Modified: 16 Feb 2021 14:11 UTC
Resource URI: https://kar.kent.ac.uk/id/eprint/79835 (The current URI for this page, for reference purposes)
Vuono, R.: https://orcid.org/0000-0002-5162-3422
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