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 TREM2R47H mutation on blood monocytes.
Bone marrow transplantation (BMT) models were used to assess the contribution of blood monocytes carrying TREM2R47H mutation to AD.
Aβ phagocytosis was compromised in mouse monocytes carrying the TREM2R47H mutation. Transplantation of bone marrow cells (BMCs) carrying TREM2R47H mutation increased cerebral Aβ burden and aggravated AD-type pathologies. Moreover, the replacement of TREM2R47H-BMCs restored monocytic Aβ phagocytosis, lowered Aβ levels in the blood and brain, and improved cognitive function.
Our study reveals that blood monocytes carrying the TREM2R47H mutation substantially contribute to the pathogenesis of AD, and correcting the TREM2R47H mutation in BMCs would be a potential therapeutic approach for those carrying this mutation.
TREM2R47H mutation compromises the Aβ phagocytosis of blood monocytes. Blood monocytes carrying TREM2R47H mutation contribute substantially to AD pathogenesis. Correction of the TREM2R47H mutation in bone marrow cells ameliorates AD pathologies and cognitive impairments.
© 2025 The Author(s). Alzheimer's & Dementia published by Wiley Periodicals LLC on behalf of Alzheimer's Association.

Oncoprotein AML1-ETO (AE) derived from t(8;21)(q22;q22) translocation is typically present in a portion of French-American-British-M2 subtype of acute myeloid leukemia (AML). Although these patients have relatively favorable prognoses, substantial numbers of them would relapse after conventional therapy. Here, we explored whether reinforcing the endogenous differentiation potential of t(8;21) AML cells would diminish the associated malignancy. In doing so, we noticed an expansion of immature erythroid blasts featured in both AML1-ETO9a (AE9a) and AE plus c-KIT (N822K) (AK) murine leukemic models. Interestingly, in the AE9a murine model, a spontaneous step-wise erythroid differentiation path, as characterized by the differential expression of CD43/c-Kit and the upregulation of several key erythroid transcription factors (TFs), accompanied the decline or loss of leukemia-initiating potential. Notably, overexpression of one of the key erythroid TFs, Ldb1, potently disrupted the repopulation of AE9a leukemic cells in vivo, suggesting a new promising intervention strategy of t(8;21) AML through enforcing their erythroid differentiation.
© 2022 Federation of American Societies for Experimental Biology.