Roles of blood monocytes carrying TREM2mutation in pathogenesis of Alzheimer's disease and its therapeutic potential in APP/PS1 mice.

Abstract

INTRODUCTION: The triggering receptor expressed on myeloid cells 2 (TREM2) arginine-47-histidine (R47H) mutation is a significant risk for Alzheimer's disease (AD) with unclear mechanisms. Previous studies focused on microglial amyloid-β (Aβ) phagocytosis with less attention on the impact of TREM2mutation on blood monocytes. METHODS: Bone marrow transplantation (BMT) models were used to assess the contribution of blood monocytes carrying TREM2mutation to AD. RESULTS: Aβ phagocytosis was compromised in mouse monocytes carrying the TREM2mutation. Transplantation of bone marrow cells (BMCs) carrying TREM2mutation increased cerebral Aβ burden and aggravated AD-type pathologies. Moreover, the replacement of TREM2-BMCs restored monocytic Aβ phagocytosis, lowered Aβ levels in the blood and brain, and improved cognitive function. DISCUSSION: Our study reveals that blood monocytes carrying the TREM2mutation substantially contribute to the pathogenesis of AD, and correcting the TREM2mutation in BMCs would be a potential therapeutic approach for those carrying this mutation. HIGHLIGHTS: TREM2mutation compromises the Aβ phagocytosis of blood monocytes. Blood monocytes carrying TREM2mutation contribute substantially to AD pathogenesis. Correction of the TREM2mutation in bone marrow cells ameliorates AD pathologies and cognitive impairments.