TREM1 facilitates microglial phagocytosis of amyloid beta.

Abstract

As the most common type of neurodegenerative disease, Alzheimer's disease (AD) is characterized by the accumulation of amyloid-β peptide (Aβ) within the brain. Triggering receptor expressed on myeloid cells (TREM) 1 is an immune receptor expressed by mononuclear phagocytes including monocytes and microglia, coupling with TYRO protein tyrosine kinase binding protein to regulate immune reactions. Emerging evidence indicates that rs6910730G, an intronic variant of TREM1, is associated with an increased Aβ neuropathology in the brains of elderly subjects, but the underlying mechanisms remain unclear. Here, using two independent cohorts of healthy individuals, we provided evidence that rs6910730G reduced the ability of human monocytes for Aβ phagocytosis, and this reduction was likely attributed to a decreased monocytic TREM1 expression. By knockdown and overexpression of Trem1 in mouse primary microglia, we showed that TREM1 facilitated microglial phagocytosis of Aβ. In support of this finding, knockdown of Trem1 in the brains of APP/PSEN1 mice increased Aβ1-42 levels and total amyloid burden, whereas selective overexpression of Trem1 on microglia or activation of Trem1 signaling by an agonistic antibody ameliorated Aβ neuropathology and rescued AD-related spatial cognitive impairments. Altogether, these findings uncover the role of TREM1 in microglial Aβ clearance, and establish TREM1 as a potential therapeutic target for AD.

• Authors: Teng Jiang, Ying-Dong Zhang, Qing Gao, Jun-Shan Zhou, Xi-Chen Zhu, Huan Lu, Jian-Quan Shi, Lan Tan, Qi Chen, Jin-Tai Yu
• Journal: Acta neuropathologica (Acta Neuropathol) Vol. 132 Issue 5 Pg. 667-683 (11 2016) ISSN: 1432-0533 [Electronic] Germany
• PMID: 27670763 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Amyloid beta-Peptides
• Amyloid beta-Protein Precursor
• Antibodies
• Membrane Glycoproteins
• PSEN1 protein, human
• Peptide Fragments
• Presenilin-1
• Receptors, Immunologic
• TREM1 protein, human
• Triggering Receptor Expressed on Myeloid Cells-1
• amyloid beta-protein (1-42)

Topics

• Aged
• Alzheimer Disease (genetics, pathology)
• Amyloid beta-Peptides (pharmacology)
• Amyloid beta-Protein Precursor (genetics)
• Animals
• Animals, Newborn
• Antibodies (pharmacology)
• Brain (cytology, pathology)
• Cells, Cultured
• Gene Expression Regulation (drug effects, genetics)
• Humans
• Male
• Maze Learning (drug effects)
• Membrane Glycoproteins (genetics, immunology, metabolism)
• Mice, Transgenic
• Microglia (metabolism)
• Middle Aged
• Monocytes (drug effects, metabolism)
• Peptide Fragments (pharmacology)
• Phagocytosis (drug effects)
• Polymorphism, Single Nucleotide (genetics)
• Presenilin-1 (genetics)
• Receptors, Immunologic (genetics, immunology, metabolism)
• Triggering Receptor Expressed on Myeloid Cells-1