Work

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

Year: 2024

Type: article

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 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.

Source: Alzheimer s & Dementia

DOI: 10.1002/alz.14402