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Prion protein N1 cleavage peptides stimulate microglial interaction with surrounding cells.

ABSTRACT: Microglia act as the protective immune cell of the brain. By surveying the tissue to identify and rectify problems, they function to maintain the health of brain cells. The prion protein N-terminal cleavage fragment, N1, has demonstrated neuroprotective activities in vitro and in vivo. This study aimed to elucidate whether N1 could modulate microglial function and, if so, determine the consequences for the surrounding tissue. Using a mixed neuronal lineage and microglia co-culture system, we showed that N1 stimulation changed overall morphology and metabolism, suggesting enhanced cellular viability. Furthermore, N1 induced an increase in Cxcl10 secretion in the co-cultures. Recombinant Cxcl10, administered exogenously, mediated the changes in the mixed neuronal lineage culture morphology and metabolism in the absence of microglia, but no effect of Cxcl10 was observed on microglia cultured on their own. Direct cell-to-cell contact was required for N1 to influence microglia in the co-cultures, and this was linked with restructuring of microglial membrane composition to include a higher GM1 content at interaction sites with surrounding cells. Our findings show that N1 can play a regulatory role in microglial function in the context of an inter-connected network of cells by changing both cellular interaction sites and cytokine secretion.

SUBMITTER: Carroll JA

PROVIDER: S-EPMC7171115 | biostudies-literature | 2020 Apr

REPOSITORIES: biostudies-literature

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Prion protein N1 cleavage peptides stimulate microglial interaction with surrounding cells.

Carroll J A JA Groveman B R BR Williams K K Moore R R Race B B Haigh C L CL

Scientific reports 20200420 1

Microglia act as the protective immune cell of the brain. By surveying the tissue to identify and rectify problems, they function to maintain the health of brain cells. The prion protein N-terminal cleavage fragment, N1, has demonstrated neuroprotective activities in vitro and in vivo. This study aimed to elucidate whether N1 could modulate microglial function and, if so, determine the consequences for the surrounding tissue. Using a mixed neuronal lineage and microglia co-culture system, we sho ...[more]

PMID: 32313035

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Project description:Prion protein aggregation is known to be modulated by macromolecules including nucleic acids. To clarify the role of nucleic acids in PrP pathology, we investigated the interaction between nucleic acids and the prion peptide (PrP)-a synthetic prion protein model peptide resembling a portion of the human prion protein in structure and function spanning amino acid residues 106-126. We used synthetic DNA lattices and natural DNA duplexes extracted from salmon (sDNA) bound with PrP and studied their interaction using distinct physical measurements. The formation of DNA lattices with PrP was visualized by atomic force microscopy (AFM) to investigate the influence of the PrP. PrP inhibited the growth of the double-crossover (DX) lattices significantly compared to the control peptide (CoP). We also conducted optical measurements such as ultraviolet-visible (UV-Vis), circular dichroism (CD), and Fourier transform infrared (FTIR) spectroscopies to validate the interaction between PrP and DNA immediately (D0) and after a 30-day incubation (D30) period. UV-Vis spectra showed variation in the absorbance intensities, specific for the binding of CoP and PrP to DNA. The CD analysis revealed the presence of various secondary structures, such as α-helices and β-sheets, in PrP- and PrP-bound sDNA complexes. The PrP-sDNA interaction was confirmed using FTIR by the change and shift of the absorption peak intensity and the alteration of PrP secondary structures in the presence of DNA. The cytotoxic effects of the PrP-bound sDNA complexes were assessed by a cytotoxicity assay in human neuroblastoma cells in culture. It confirmed that PrP with sDNA was less cytotoxic than CoP. This study provides new applications for DNA molecules by investigating their effect in complex with aggregated proteins. Our study unequivocally showed the beneficial effect of the interaction between DNA and the pathological prion protein. It therefore provides valuable information to exploit this effect in the development of potential therapeutics. Moreover, our work might serve as a basis for further studies investigating the role of DNA interactions with other amyloidogenic proteins.

Dataset Information

Prion protein N1 cleavage peptides stimulate microglial interaction with surrounding cells.

Publications

Prion protein N1 cleavage peptides stimulate microglial interaction with surrounding cells.

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