Dataset Information

Human Plasma Protein Corona of A? Amyloid and Its Impact on Islet Amyloid Polypeptide Cross-Seeding.

ABSTRACT: Alzheimer's disease (AD) is the most severe form of neurological disorder, characterized by the presence of extracellular amyloid-? (A?) plaques and intracellular tau tangles. For decades, therapeutic strategies against the pathological symptoms of AD have often relied on the delivery of monoclonal antibodies to target specifically A? amyloid or oligomers, largely to no avail. A? can be traced in the brain as well as in cerebrospinal fluid and the circulation, giving rise to abundant opportunities to interact with their environmental proteins. Using liquid chromatography tandem-mass spectrometry, here we identified for the first time the protein coronae of the two major amyloid forms of A?-A?_1-42 and A?_1-40-exposed to human blood plasma. Out of the proteins identified in all groups, 58 proteins were unique to the A?_1-42 samples and 31 proteins unique to the A?_1-40 samples. Both fibrillar coronae consisted of proteins significant in complement activation, inflammation, and protein metabolic pathways involved in the pathology of AD. Structure-wise, the coronal proteins often possessed multidomains of high flexibility to maximize their association with the amyloid fibrils. The protein corona hindered recognition of A?_1-42 fibrils by their structurally specific antibodies and accelerated the aggregation but not the ?-cell toxicity of human islet amyloid polypeptide, the peptide associated with type 2 diabetes. This study highlights the importance of understanding the structural, functional, and pathological implications of the amyloid protein corona for the development of therapeutics against AD and a range of amyloid diseases.

SUBMITTER: Nandakumar A

PROVIDER: S-EPMC7067050 | biostudies-literature | 2020 Feb

REPOSITORIES: biostudies-literature

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Publications

Human Plasma Protein Corona of Aβ Amyloid and Its Impact on Islet Amyloid Polypeptide Cross-Seeding.

Nandakumar Aparna A Xing Yanting Y Aranha Ritchlynn R RR Faridi Ava A Kakinen Aleksandr A Javed Ibrahim I Koppel Kairi K Pilkington Emily H EH Purcell Anthony Wayne AW Davis Thomas P TP Faridi Pouya P Ding Feng F Ke Pu Chun PC

Biomacromolecules 20200121 2

Alzheimer's disease (AD) is the most severe form of neurological disorder, characterized by the presence of extracellular amyloid-β (Aβ) plaques and intracellular tau tangles. For decades, therapeutic strategies against the pathological symptoms of AD have often relied on the delivery of monoclonal antibodies to target specifically Aβ amyloid or oligomers, largely to no avail. Aβ can be traced in the brain as well as in cerebrospinal fluid and the circulation, giving rise to abundant opportuniti ...[more]

PMID: 31909987

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Project description:Complement inhibitor C4b-binding protein (C4BP) is synthesized in liver and pancreas and composed of 7 identical alpha chains and one unique beta chain. We showed previously that C4BP binds islet amyloid polypeptide (IAPP) and affects fibril formation in vitro. Now we found that polymeric C4BP inhibited lysis of human erythrocytes incubated with monomeric IAPP while no erythrocyte lysis was observed after incubation with preformed IAPP fibrils. In contrast, monomeric alpha chain of C4BP had significantly reduced activity. Further, addition of monomeric IAPP to a rat insulinoma cell line (INS-1) resulted in decreased cell viability, which was restored in the presence of physiological concentrations of C4BP. Accordingly, addition of C4BP rescued the ability of INS-1 cells and isolated rat islets to respond to glucose stimulation with insulin secretion, which was impaired in the presence of IAPP alone. C4BP was internalized together with IAPP into INS-1 cells and therefore we aimed to study its effect on gene expression. Pathway analyses of mRNA expression microarray data indicated that cells exposed to C4BP and IAPP in comparison to IAPP alone increased expression of genes involved in cholesterol synthesis. Depletion of cholesterol through methyl-Î²-cyclodextrin or cholesterol oxidase abolished the protective effect of C4BP on IAPP cytotoxicity of INS-1 cells. Also, inhibition of phosphoinositide 3-kinase but not NF-ÎºB had a similar effect. Taken together, one of the mechanisms by which C4BP protects beta-cells from IAPP cytotoxicity is by enhancing cholesterol synthesis. The INS-1 cells were grown as 5 separate clones for 10 passages before plating in a 12-well plate (Nunc) at 100.000 cells per well and grown in complete RPMI 1640 medium to 70% confluency for approximately 48 h. The cells were then challenged by adding 77 Î¼M monomeric IAPP alone or together with C4BP (0.6 Î¼M). DMSO (1%) used as solvent for IAPP as well as C4BP (0.6 Î¼M) alone were used as controls. RNA was extracted after 10h incubation and analysis carried out using Rat Gene 2.0 array chip (Affymetrix).

Dataset Information

Human Plasma Protein Corona of A? Amyloid and Its Impact on Islet Amyloid Polypeptide Cross-Seeding.

Publications

Human Plasma Protein Corona of Aβ Amyloid and Its Impact on Islet Amyloid Polypeptide Cross-Seeding.

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