Evidence that the Human Innate Immune Peptide LL-37 may be a Binding Partner of Amyloid-? and Inhibitor of Fibril Assembly.

ABSTRACT: Identifying physiologically relevant binding partners of amyloid-? (A?) 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.We present in vitro experimental evidence and discuss findings supporting a novel hypothesis that LL-37 binds to A?42 and can modulate A? fibril formation.Specific interactions between LL-37 and A? (with A? 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, A?42 alone, and LL-37/A? complexes were evaluated in human microglia and neuroblastoma cell lines (SH-SY5Y).SPRi shows binding specificity between LL-37 and A?, while TEM shows that LL-37 inhibits A?42 fibril formation, particularly A?'s ability to form long, straight fibrils characteristic of AD. CD reveals that LL-37 prevents A?42 from adopting its typical ?-type secondary structure. Microglia-mediated toxicities of LL-37 and A?42 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.Based on this body of evidence, we propose that LL-37 and A?42 may be natural binding partners, which implies that balanced (or unbalanced) spatiotemporal expression of the two peptides could impact AD initiation and progression.

SUBMITTER: De Lorenzi E 

PROVIDER: S-EPMC5611894 | biostudies-other | 2017

REPOSITORIES: biostudies-other