Background: Identifying physiologically relevant binding partners of amyloid-beta (Abeta) that modulate in vivo fibril formation may yield new insights into Alzheimer’s disease (AD) etiology. Human cathelicidin peptide, LL-37, is an innate immune effector and modulator, ubiquitous in human tissues and expressed in myriad cell types. Objective: We present in vitro experimental evidence and discuss findings supporting a novel hypothesis that LL-37 binds to Abeta42 and can modulate Abeta fibril formation. Methods: Specific interactions between LL-37 and Abeta (with Abeta in different aggregation states, assessed by capillary electrophoresis) were demonstrated by surface plasmon resonance imaging (SPRi). Morphological and structural changes were investigated by transmission electron microscopy (TEM) and circular dichroism (CD) spectroscopy. Neuroinflammatory and cytotoxic effects of LL-37 alone,Abeta42 alone, and LL-37/Abeta complexes were evaluated in human microglia and neuroblastoma cell lines (SH-SY5Y). Results: SPRi shows binding specificity between LL-37 and Abeta, while TEM shows that LL-37 inhibits Abeta42 fibril formation, particularlyAbeta’s ability to form long, straight fibrils characteristic of AD.CDreveals that LL-37 prevents Abeta42 from adopting its typical -type secondary structure. Microglia-mediated toxicities of LL-37 and Abeta42 to neurons are greatly attenuated when the two peptides are co-incubated prior to addition. We discuss the complementary biophysical characteristics and AD-related biological activities of these two peptides. Conclusion: Based on this body of evidence, we propose that LL-37 and Abeta42 may be natural binding partners, which implies that balanced (or unbalanced) spatiotemporal expression of the two peptides could impact AD initiation and progression.

Evidence that the human innate immune peptide LL-37 may be a binding partner of amyloid-beta and inhibitor of fibril assembly

DE LORENZI, ERSILIA;COLOMBO, RAFFAELLA;BISCEGLIA, FEDERICA;
2017-01-01

Abstract

Background: Identifying physiologically relevant binding partners of amyloid-beta (Abeta) that modulate in vivo fibril formation may yield new insights into Alzheimer’s disease (AD) etiology. Human cathelicidin peptide, LL-37, is an innate immune effector and modulator, ubiquitous in human tissues and expressed in myriad cell types. Objective: We present in vitro experimental evidence and discuss findings supporting a novel hypothesis that LL-37 binds to Abeta42 and can modulate Abeta fibril formation. Methods: Specific interactions between LL-37 and Abeta (with Abeta in different aggregation states, assessed by capillary electrophoresis) were demonstrated by surface plasmon resonance imaging (SPRi). Morphological and structural changes were investigated by transmission electron microscopy (TEM) and circular dichroism (CD) spectroscopy. Neuroinflammatory and cytotoxic effects of LL-37 alone,Abeta42 alone, and LL-37/Abeta complexes were evaluated in human microglia and neuroblastoma cell lines (SH-SY5Y). Results: SPRi shows binding specificity between LL-37 and Abeta, while TEM shows that LL-37 inhibits Abeta42 fibril formation, particularlyAbeta’s ability to form long, straight fibrils characteristic of AD.CDreveals that LL-37 prevents Abeta42 from adopting its typical -type secondary structure. Microglia-mediated toxicities of LL-37 and Abeta42 to neurons are greatly attenuated when the two peptides are co-incubated prior to addition. We discuss the complementary biophysical characteristics and AD-related biological activities of these two peptides. Conclusion: Based on this body of evidence, we propose that LL-37 and Abeta42 may be natural binding partners, which implies that balanced (or unbalanced) spatiotemporal expression of the two peptides could impact AD initiation and progression.
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11571/1192300
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