Human Umbilical Cord Blood-Derived Monocytes Improve Cognitive Deficits and Reduce Amyloid-β Pathology in PSAPP Mice

Abstract

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 Aβ-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 Aβ pathology-ameliorating activities. Most importantly, we found that compared with CB-M, aged monocytes showed an ineffective phagocytosis of Aβ, while exogenous soluble amyloid precursor protein α (sAPPα) could reverse this deficiency. Pretreating monocytes with sAPPα upregulates Aβ internalization. Our further studies suggested that sAPPα could form a heterodimer with Aβs, with the APP672–688 (Aβ1–16) region being responsible for this effect. This in turn promoted binding of these heterodimers to monocyte scavenger receptors and thus promoted enhanced Aβ clearance. In summary, our findings suggest an interesting hypothesis that peripheral monocytes contribute to Aβ clearance through heterodimerization of sAPPα with Aβ. Further, declined or impaired sAPPα production, or reduced heterodimerization with Aβ, would cause a deficiency in Aβ clearance and thus accelerate the pathogenesis of AD.

Restoring Soluble Amyloid Precursor Protein α Functions as a Potential Treatment for Alzheimer's Disease

“…It is plausible that sAPPa shuttles Ab to the endothelial LRP1 at the abluminal side and shifts Ab out of the brain to the periphery, as shown in Figure 2b. In accordance with this hypothesis, our group (Darlington et al, 2015) found that sAPPa forms a complex with Ab (corresponding to APP 672-688 region) and thereby enhances phagocytosis by monocytes. In addition, sAPPa enhances scavenger receptor class A (SR-A)mediated phagocytosis of Ab by microglia (brain) and monocytes (peripheral system), as shown in Figure. 2c.…”

“…Interestingly, our recent work indicates that sAPPα forms a complex with the Aβ 1–16 (corresponding to APP672–688) region, which augments the binding of this heterodimer complex with SR‐A receptor. Our conclusion is that scavenger receptor SR‐A seems to be crucial for sAPPα‐mediated clearance of Aβ (Darlington et al, ).…”

“…While identifying the mechanism, further studies indicated that cord blood monocytes might have their own α‐secretase or activate an endogenous α‐secretase enzyme in the PSAPP mouse model. Interestingly, exogenous sAPPα reversed the deficiency of phagocytosis shown by aged blood monocytes (Darlington et al, ). Thus, restoration of sAPPα levels in the brain by shifting the amyloidogenic toward the nonamyloidogenic pathway could ameliorate AD‐related amyloid and tau pathology, neuronal loss, and cognitive impairment.…”

Plasma derived from human umbilical cord blood: Potential cell‐additive or cell‐substitute therapeutic for neurodegenerative diseases

“…| 6163 IL-8 and VEGF might be a beneficial treatment for repair of the damaged blood-brain barrier and/or blood-spinal cord barrier in patients with ALS, [41][42][43][44] AD, 45 Parkinson's disease 46 and multiple sclerosis. 47 Finally, our in vitro studies showed significantly increased viabil- In this context, numerous studies have shown neuroprotective effects of MNC hUCB administered into animal models of ALS, [48][49][50][51] AD, [52][53][54] Parkinson's disease, 55 ischaemic stroke 56,57 and traumatic brain injury. 58 been observed from intravenous administration of CBP into rats modelling acute ischaemic stroke 5 or into an animal model of ageing.…”

A systemic view of Alzheimer disease — insights from amyloid-β metabolism beyond the brain

“…Of note, in transgenic mice with AD, expression of Aβ scavenger receptors and Aβ-degrading enzymes in circulating mononuclear phagocytes decreases substantially as these mice age 42 , and the phagocytic functions of these cells are impaired in both mice and humans with AD [43][44][45] . Infusion of monocytes derived from peripheral human umbilical cord blood reduces the Aβ burden and improves cognitive deficits in a mouse model of AD 46 , implying that peripheral mononuclear phagocytes have an important role in Aβ clearance. Promoting the phagocytic function of peripheral blood monocytes or promoting the recruitment of peripheral macrophages into the brain might, therefore, improve Aβ clearance in the brain 47 , although the existence of conflicting data 48 renders this approach controversial.…”