Peripheral clearance of amyloid β peptide by complement C3-dependent adherence to erythrocytes

Rogers, Joseph; Li, Rena; Mastroeni, Diego; Grover, Andrew; Leonard, Brian; Ahern, Geoffrey L.; Cao, Phillip; Kolody, Heather; Vedders, Linda; Kolb, William P.; Sabbagh, Marwan N.

doi:10.1016/j.neurobiolaging.2005.09.043

Cited by 158 publications

(137 citation statements)

References 18 publications

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“…Blood levels of albumin, an Aβ carrier, are reduced in patients with AD 63 . The quantity and function of erythrocytes (another Aβ carrier) are also altered in such patients, and their erythrocytes show compromised binding of Aβ 64,65 . In addition, the activity of Aβ-degrading enzymes in serum is thought to be decreased in AD 28 .…”

Section: Blood Abnormalitiesmentioning

confidence: 99%

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

et al. 2017

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The global burden of Alzheimer disease (AD), already the most common type of dementia, is expected to increase still further owing to population ageing. AD not only causes severe distress for patients and caregivers, but also results in a large economic burden on society. Current major challenges in AD include the lack of reliable biomarkers for its early diagnosis, as well as the lack of effective preventive strategies and treatments 1,2 . Thus, increased understanding of the molecular patho genesis of AD could lead to the development of improved diagnostic and therapeutic strategies.AD is conventionally regarded as a CNS disorder. However, increasing experimental, epidemiological and clinical evidence has suggested that manifestations of AD extend beyond the brain. These systemic alterations might not be simply secondary effects of the cerebral degeneration seen in AD, but could reflect under lying processes linked to progression of the disease. AD pathogenesis is complex, involving abnormal amyloid-β (Aβ) metabolism, tau hyperphosphorylation, oxidative stress, reactive glial and microglial changes, and other pathological events. Given that Aβ is a major hallmark of AD and a fertile area of research in this disease, this Review focuses on the systemic role of Aβ in AD. We discuss the communication between peripheral and central pools of Aβ, and describe interactions between systemic abnormalities and AD pathogenesis in the brain. We review emerging findings of associations between systemic abnormalities and Aβ metabolism, and describe how these associations might interact with or reflect on the central pathways of Aβ production and clearance. On the basis of these findings, we suggest that interactions between the brain and the periphery might have a crucial role in the development and progression of AD. Aβ biogenesis and catabolismA steady accrual of data from laboratories and clinics is providing increasing support for the concept that an imbalance between the production and clearance of Aβ is a very early (and often initiating) factor in AD 3 . Normal metabolism of Aβ and maintenance of the homeostatic balance between Aβ production and clearance is, therefore, essential to maintain brain health. In fact, physiological metabolism of Aβ occurs not only in the brain but also in the periphery, and communication between these regions is possible (FIG. 1). Central and peripheral production of AβAβ is derived from the proteolytic cleavage of amyloid precursor protein (APP), which is expressed not only in brain cells, including neurons, astrocytes and microglia, but also in peripheral organs and tissues, such as the Abstract | Alzheimer disease (AD) is the most common type of dementia, and is currently incurable; existing treatments for AD produce only a modest amelioration of symptoms. Research into this disease has conventionally focused on the CNS. However, several peripheral and systemic abnormalities are now understood to be linked to AD, and our understanding of how these alterations contribute to AD is becom...

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Section: Blood Abnormalitiesmentioning

confidence: 99%

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

et al. 2017

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“…It has been proposed that CR1 may participate in Ab peptides clearance, which is supported by the observation that circulating Ab42 adheres to erythrocytes, a process that is impaired in Alzheimer's disease cases (64). In a recent study, Keenan et al (65) reported that a CR1 polymorphism resulting in substitution of a threonine for a serine residue at position 1610 of CCP25 of CR1 was associated with episodic memory decline in Alzheimer's disease.…”

Section: Discussionmentioning

confidence: 96%

Deciphering Complement Receptor Type 1 Interactions with Recognition Proteins of the Lectin Complement Pathway

Jacquet

Lacroix²,

Ancelet³

et al. 2013

The Journal of Immunology

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Complement receptor type 1 (CR1) is a membrane receptor expressed on a wide range of cells. It is involved in immune complex clearance, phagocytosis, and complement regulation. Its ectodomain is composed of 30 complement control protein (CCP) modules, organized into four long homologous repeats (A–D). In addition to its main ligands C3b and C4b, CR1 was reported to interact with C1q and mannan-binding lectin (MBL) likely through its C-terminal region (CCP22–30). To decipher the interaction of human CR1 with the recognition proteins of the lectin complement pathway, a recombinant fragment encompassing CCP22–30 was expressed in eukaryotic cells, and its interaction with human MBL and ficolins was investigated using surface plasmon resonance spectroscopy. MBL and L-ficolin were shown to interact with immobilized soluble CR1 and CR1 CCP22–30 with apparent dissociation constants in the nanomolar range, indicative of high affinity. The binding site for CR1 was located at or near the MBL-associated serine protease (MASP) binding site in the collagen stalks of MBL and L-ficolin, as shown by competition experiments with MASP-3. Accordingly, the mutation of an MBL conserved lysine residue essential for MASP binding (K55) abolished binding to soluble CR1 and CCP22–30. The CR1 binding site for MBL/ficolins was mapped to CCP24–25 of long homologous repeat D using deletion mutants. In conclusion, we show that ficolins are new CR1 ligands and propose that MBL/L-ficolin binding involves major ionic interactions between conserved lysine residues of their collagen stalks and surface exposed acidic residues located in CR1 CCP24 and/or CCP25.

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“…Indeed, over 50 percent of Aβ in circulation within the vascular compartment may be bound to RBCs [79]. It is clear that RBCs in AD show morphological and biochemical evidence of injury that can lead to hemolysis [19,23,32,41,48,76,78], although it is not clear if hemolytic anemia is associated with AD [8,26,64,68,73].…”

Section: Discussionmentioning

confidence: 99%

“…Circulating blood cells are exposed to both soluble Aβ1-40/42 and to Aβ aggregates associated with the luminal surfaces of cerebral microvessels (e.g., CAA) [76,79]. In vitro, Aβ25-35 induces rapid lysis of human erythrocytes, whereas Aβ1-42 induces delayed lysis of erythrocytes that can be attenuated by antioxidants [63].…”

Section: Aβ Damage To Erythrocytesmentioning

confidence: 99%

“…In vitro, Aβ25-35 induces rapid lysis of human erythrocytes, whereas Aβ1-42 induces delayed lysis of erythrocytes that can be attenuated by antioxidants [63]. Human red blood cells (RBC) that bind fibrillar amyloid in vitro and in vivo show increased RBC hemoglobin oxidative modification and endothelial adhesion [27,42,76,79]. AD patients have increased RBC membrane injury suggesting the increased potential for erythrocyte lysis and liberation of Hb when the cells are exposed to Aβ1-42 [11,36,63,92].…”

Section: Aβ Damage To Erythrocytesmentioning

confidence: 99%

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Hemoglobin binding to Aβ and HBG2 SNP association suggest a role in Alzheimer's disease

Perry

Gearhart

Wiener

et al. 2008

Neurobiology of Aging

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From a normal human brain phage display library screen we identified the gamma (A)-globin chain of fetal hemoglobin (Hb F) as a protein that bound strongly to Aβ1-42. We showed the oxidized form 1 These authors are co-corresponding authors for all stages of refereeing and publication and contributed equally to this work. Rodney T. Perry; Rm. 210H, 1665 University Blvd.; University of Alabama at Birmingham, Birmingham, USA; Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. Disclosure Statement:I so state for myself and on behalf of the other authors on the manuscript, Hemoglobin binding to Aβ and HBG2 SNP association suggest a role in Alzheimer's disease, that we have no conflicts and sources of funding that influence the results of this paper, the data is not published or submitted elsewhere, and that appropriate approval and procedures were used concerning human subjects. I also verify that all authors on this manuscript have reviewed the contents of the manuscript, approve of its contents, and validate the accuracy of the data. NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author Manuscript of adult Hb (metHb A) binds with greater affinity to Aβ1-42 than metHb F. MetHb is more toxic than oxyhemoglobin because it loses its heme group more readily. Free Hb and heme readily damage vascular endothelial cells similar to Alzheimer's disease (AD) vascular pathology. The XmnI polymorphism (C→T) at −158 of the gamma (G)-globin promoter region can contribute to increased Hb F expression. Using family-based association testing, we found a significant protective association of this polymorphism in the NIMH sibling dataset (n=489) in families, with at least two affected and one unaffected sibling (p=0.006), with an age of onset >50 years (p=0.010) and >65 years (p=0.013), and families not homozygous for the APOE4 allele (p=0.041). We hypothesize that Hb F may be less toxic than adult Hb in its interaction with Aβ and may protect against the development of AD.

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Peripheral clearance of amyloid β peptide by complement C3-dependent adherence to erythrocytes

Cited by 158 publications

References 18 publications

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

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

Deciphering Complement Receptor Type 1 Interactions with Recognition Proteins of the Lectin Complement Pathway

Hemoglobin binding to Aβ and HBG2 SNP association suggest a role in Alzheimer's disease

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