Roles of blood monocytes carrying TREM2^R47H mutation in pathogenesis of Alzheimer's disease and its therapeutic potential in APP/PS1 mice

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 TREM2^R47H mutation on blood monocytes.

Methods: Bone marrow transplantation (BMT) models were used to assess the contribution of blood monocytes carrying TREM2^R47H mutation to AD.

Results: Aβ phagocytosis was compromised in mouse monocytes carrying the TREM2^R47H mutation. Transplantation of bone marrow cells (BMCs) carrying TREM2^R47H mutation increased cerebral Aβ burden and aggravated AD-type pathologies. Moreover, the replacement of TREM2^R47H-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 TREM2^R47H mutation substantially contribute to the pathogenesis of AD, and correcting the TREM2^R47H mutation in BMCs would be a potential therapeutic approach for those carrying this mutation.

Highlights: TREM2^R47H mutation compromises the Aβ phagocytosis of blood monocytes. Blood monocytes carrying TREM2^R47H mutation contribute substantially to AD pathogenesis. Correction of the TREM2^R47H mutation in bone marrow cells ameliorates AD pathologies and cognitive impairments.