Human Umbilical Cord Blood-Derived Monocytes Improve Cognitive Deficits and Reduce Amyloid-β Pathology in PSAPP Mice (Publication with Expression of Concern. See vol. 31, 2022)

Alzheimer's disease (AD) is the fourth major cause of mortality in the elderly in the US and the leading cause of dementia worldwide. While pharmacological targets have been discovered, there are no true disease-modifying therapies. We have recently discovered that multiple low-dose infusions of human umbilical cord blood cells (HUCBCs) ameliorate cognitive impairments and reduce A beta-associated neuropathology in PSAPP transgenic mice. However, the mechanism for these effects of HUCBCs remains unclear. In the present study, we examined whether monocytes, as important components of HUCBCs, would have beneficial outcomes on the reduction of AD-like pathology and associated cognitive impairments in PSAPP transgenic AD model mice. PSAPP mice and their wild-type littermates were treated monthly with an infusion of peripheral human umbilical cord blood cell (HUCBC)-derived monocytes over a period of 2 and 4 months, followed by behavioral evaluations, biochemical, and histological analyses. The principal findings of the present study confirmed that monocytes derived from HUCBCs (CB-M) play a central role in HUCBC-mediated cognition-enhancing and A beta pathology-ameliorating activities. Most importantly, we found that compared with CB-M, aged monocytes showed an ineffective phagocytosis of A beta, while exogenous soluble amyloid precursor protein alpha (sAPP alpha) could reverse this deficiency. Pretreating monocytes with sAPP alpha upregulates A beta internalization. Our further studies suggested that sAPP alpha could form a heterodimer with A beta s, with the APP(672-688) (A beta(1-16)) region being responsible for this effect. This in turn promoted binding of these heterodimers to monocyte scavenger receptors and thus promoted enhanced A beta clearance. In summary, our findings suggest an interesting hypothesis that peripheral monocytes contribute to A beta clearance through heterodimerization of sAPP alpha with A beta. Further, declined or impaired sAPP alpha production, or reduced heterodimerization with A beta, would cause a deficiency in A beta clearance and thus accelerate the pathogenesis of AD.