Peripheral complement interactions with amyloid β peptide: Erythrocyte clearance mechanisms

Abstract

INTRODUCTION Although Aβ is cleared from brain to CSF and the peripheral circulation, mechanisms for its removal from blood remain unresolved. Primates have uniquely evolved a highly effective peripheral clearance mechanism for pathogens, immune adherence, in which erythrocyte complement receptor 1 (CR1) plays a major role. METHODS Multidisciplinary methods were employed to demonstrate immune adherence capture of Aβ by erythrocytes and its deficiency in Alzheimer’s disease (AD). RESULTS Aβ was shown to be subject to immune adherence at every step in the pathway. Aβ dose-dependently activated serum complement. Complement-opsonized Aβ was captured by erythrocytes via CR1. Erythrocytes, Aβ, and hepatic Kupffer cells co-localized in human liver. Significant deficits in erythrocyte Aβ were found in AD and MCI patients. DISCUSSION CR1 polymorphisms elevate AD risk and >80% of human CR1 is vested in erythrocytes to subserve immune adherence. The present results suggest that this pathway is pathophysiologically relevant in AD.

Contribution of Neurons and Glial Cells to Complement-Mediated Synapse Removal during Development, Aging and in Alzheimer’s Disease

“…In the periphery, CR1 is mainly expressed by erythrocytes and is involved in the clearance of complement-opsonized pathogens. It has been reported that peripheral A β is opsonized by the complement and captured by erythrocyte and monocyte/macrophage CR1 [ 21 , 93 ]. In AD patients, capture of A β by erythrocytes is reduced [ 21 , 93 ] and A β immunotherapy improves this clearance mechanism in vitro and in living primates [ 21 ].…”

Hepatic macrophages in liver homeostasis and diseases-diversity, plasticity and therapeutic opportunities

“…17 Functionality of hepatic macrophages during homeostasis KCs play a critical role in maintaining homeostasis of the liver and the whole body through five major functions. These include (i) clearance of cellular debris and metabolic waste, [18][19][20] (ii) maintenance of iron homeostasis via phagocytosis of red blood cells (RBCs) and the subsequent recycling of iron, [21][22][23][24] (iii) regulation of cholesterol homeostasis through the production of cholesteryl ester transfer protein, which is important for decreasing circulating high-density lipoprotein-cholesterol levels and increasing very low-density lipoprotein-cholesterol levels, 25 (iv) mediation of antimicrobial defense, 26,27 and (v) promotion of immunological tolerance. 28,29 Clearance of damaged or aged RBCs is crucial for systemic homeostasis.…”

New tricks for an ancient system: Physiological and pathological roles of complement in the CNS

“…However, no significant differences in CR1 or sCR1 was detected in brain or plasma respectively, of individuals harboring either the rs4844609 or rs6656401 polymorphisms [113]. Additional studies by Rogers and colleagues provided evidence that CR1 on red blood cells could participate in CR1-mediated clearance of Aß from blood [114]. Furthermore, Aß capture by red blood cells (CR1 mediated) was enhanced in vitro by the presence of anti-Aß and complement (which would increase C3b association with fibrillar amyloid), and further enhanced by intravenously administration of anti-Aß in nonhuman primates [115].…”