Amyloid-β Peptides Interact with Plasma Proteins and Erythrocytes: Implications for Their Quantitation in Plasma

Kuo, Yu Min; Kokjohn, Tyler A.; Kalback, Walter M.; Luehrs, Dean C.; Galasko, Douglas; Chevallier, Nathalie; Koo, Edward H.; Emmerling, Mark R.; Roher, Alex E.

doi:10.1006/bbrc.2000.2222

Cited by 209 publications

(185 citation statements)

References 41 publications

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“…In fact, several peripheral tissues or organs participate in Aβ catabolism and constitute potential Aβ clearance pathways. These include uptake and phagocytosis or endocytosis by monocytes, macrophages, neutrophils, lymphocytes, and hepatocytes 24,25 ; excretion via bile or urine 26,27 ; proteolytic degradation by Aβ-degrading enzymes 28 ; and clearance from blood mediated by Aβ-binding proteins and cells, such as erythrocytes, albumin, antithrombin III and lipoproteins, including apolipoprotein E (ApoE) and apolipoprotein J (ApoJ) 11,12 . These central and peripheral pathways might interact with each other and work synergistically to clear Aβ from the brain.…”

Section: Central and Peripheral Clearance Of Aβmentioning

confidence: 99%

“…One possible interpretation is that APP processing in peripheral cells probably occurs via α-cleavage (rather than the β-cleavage used in neurons) 9,10 , resulting in decreased peripheral production of Aβ. Another explanation for the lower Aβ levels in the periphery is that the periphery contains abundant Aβ-binding proteins (lipoproteins and albumin) 11 and Aβ-binding cells, such as erythrocytes 12 , which all contribute to Aβ transportation and clearance. Additionally, the high volume of the circulatory system and the blood-dilution effect efficiently reduce systemic Aβ concentrations.…”

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confidence: 99%

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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: Central and Peripheral Clearance Of Aβmentioning

confidence: 99%

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confidence: 99%

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

et al. 2017

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“…Moreover, the new dimeric binder demonstrated retained melting temperature as well as complete refolding ability after heating. The new high-affinity Affibody was also able to capture aggregation prone Ab 1-42 peptides at concentrations reflecting physiologically relevant serum levels [30][31][32]. Altogether, we believe that these results demonstrate and motivate preclinical in vivo investigations of the new Ab-binding Affibody in mouse models with AD-Ab pathology.…”

Section: A Truncated and Dimeric Format Of An Affibody Library On Bacmentioning

confidence: 81%

“…It has been shown that there is a correlation between the affinity of peripherally-administered Ab-specific agents and the efflux of Ab from the brain to the serum [29]. As levels of Ab peptides in the blood are low (subnanomolar) [30][31][32][33][34], it is probably critical to use capturing-agents of high affinity for such applications.It has previously been demonstrated that staphylococcal cell surface display in combination with fluorescenceactivated cell sorting (FACS) is well suited for combinatorial affinity maturation efforts, since it allows for high precision affinity discrimination between binders [35][36][37][38]. Recently, the method was used for affinity maturation of a HER3-specific Affibody, and generated binders with picomolar affinities [39].…”

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confidence: 99%

A truncated and dimeric format of an Affibody library on bacteria enables FACS‐mediated isolation of amyloid‐beta aggregation inhibitors with subnanomolar affinity

Lindberg

Härd

Löfblom

et al. 2015

Biotechnology Journal

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The amyloid hypothesis suggests that accumulation of amyloid b (Ab) peptides in the brain is involved in development of Alzheimer's disease. We previously generated a small dimeric affinity protein that inhibited Ab aggregation by sequestering the aggregation prone parts of the peptide. The affinity protein is originally based on the Affibody scaffold, but is evolved to a distinct interaction mechanism involving complex structural rearrangement in both the Ab peptide and the affinity proteins upon binding. The aim of this study was to decrease the size of the dimeric affinity protein and significantly improve its affinity for the Ab peptide to increase its potential as a future therapeutic agent. We combined a rational design approach with combinatorial protein engineering to generate two different affinity maturation libraries. The libraries were displayed on staphylococcal cells and high-affinity Ab-binding molecules were isolated using flow-cytometric sorting. The best performing candidate binds Ab with a K D value of around 300 pM, corresponding to a 50-fold improvement in affinity relative to the first-generation binder. The new dimeric Affibody molecule was shown to capture Ab 1-42 peptides from spiked E. coli lysate. Altogether, our results demonstrate successful engineering of this complex binder for increased affinity to the Ab peptide. Biotechnology JournalBiotechnol. J. 2015, 10, 1707-1718 therapies [8,16,17]. Alternative scaffold-proteins are in general much smaller than full-length antibodies and can usually be engineered into multivalent as well as multispecific units with an overall size that remain smaller than the conventional antibody [17,18]. Such features can potentially improve in vivo biodistribution of the agent [19][20][21][22]. One type alternative binding-protein that has been investigated for various diagnostic and therapeutic applications is the small three-helical bundle Affibody molecule (6.5 kDa) [17,23]. We previously generated an Affibody molecule (denoted Z Ab3 ) targeting monomeric Ab with a 17 nM affinity, as determined by isothermal titration calorimetry (ITC) and confirmed by surface plasmon resonance SPR [24][25][26]. Although this binder is based on the Affibody scaffold, it has evolved to adopt a unique and complex binding mechanism that is potentially more efficient for interactions with aggregation-prone peptides. Structural analysis has shown that two identical disulfide-linked Affibody units encapsulate one Ab peptide, and that both the Affibody domains and the Ab peptide undergo structural rearrangement upon binding. The Ab peptide folds into a b-hairpin structure, allowing the first α-helices in both Affibody molecules to adopt a b-sheet structure with unstructured N-termini [25,27]. In a recent in vivo study using an Ab-transgenic fruit fly model of AD, it was demonstrated that the Z Ab3 Affibody molecule efficiently inhibits the formation of Ab aggregates, thereby abolishing the neurotoxic effects and restoring the life span of the flies [25,28].For further po...

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“…Some of the retarding proteins may be of direct biological relevance by colocalization with Aβ in vivo. 26,27 The retarding effects are often rationalized in terms of interactions involving hydrophobic groups due to the amphiphatic properties of Aβ, and the presence of exposed hydrophobic areas on several of the proteins that bind to Aβ or retard the aggregation process. 19,21−23 The current work investigated the effects of hydrophilic proteins on the aggregation of Aβ(M1−40), hereafter Aβ40, and Aβ(M1−42), hereafter Aβ42.…”

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confidence: 99%

Charge Dependent Retardation of Amyloid β Aggregation by Hydrophilic Proteins

Assarsson

Hellstrand

Cabaleiro-Lago

et al. 2014

ACS Chem. Neurosci.

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The aggregation of amyloid β peptides (Aβ) into amyloid fibrils is implicated in the pathology of Alzheimer's disease. In light of the increasing number of proteins reported to retard Aβ fibril formation, we investigated the influence of small hydrophilic model proteins of different charge on Aβ aggregation kinetics and their interaction with Aβ. We followed the amyloid fibril formation of Aβ40 and Aβ42 using thioflavin T fluorescence in the presence of six charge variants of calbindin D 9k and singlechain monellin. The formation of fibrils was verified with transmission electron microscopy. We observe retardation of the aggregation process from proteins with net charge +8, +2, −2, and −4, whereas no effect is observed for proteins with net charge of −6 and −8. The single-chain monellin mutant with the highest net charge, scMN+8, has the largest retarding effect on the amyloid fibril formation process, which is noticeably delayed at as low as a 0.01:1 scMN+8 to Aβ40 molar ratio. scMN+8 is also the mutant with the fastest association to Aβ40 as detected by surface plasmon resonance, although all retarding variants of calbindin D 9k and single-chain monellin bind to Aβ40.

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Amyloid-β Peptides Interact with Plasma Proteins and Erythrocytes: Implications for Their Quantitation in Plasma

Cited by 209 publications

References 41 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

A truncated and dimeric format of an Affibody library on bacteria enables FACS‐mediated isolation of amyloid‐beta aggregation inhibitors with subnanomolar affinity

Charge Dependent Retardation of Amyloid β Aggregation by Hydrophilic Proteins

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