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

Ersilia De Lorenzi, Marcella Chiari, Raffaella Colombo, Marina Cretich, Laura Sola, Renzo Vanna, Paola Gagni, Federica Bisceglia, Carlo Morasso, Jennifer S. Lin, Moonhee Lee, Patrick L. Mcgeer, Annelise E. Barron

Research output: Contribution to journalArticle

7 Citations (Scopus)

Abstract

Background: Identifying physiologically relevant binding partners of amyloid-β (Aβ) 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 Aβ42 and can modulate Aβ fibril formation. Methods: Specific interactions between LL-37 and Aβ (with Aβ 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,Aβ42 alone, and LL-37/Aβ complexes were evaluated in human microglia and neuroblastoma cell lines (SH-SY5Y). Results: SPRi shows binding specificity between LL-37 and Aβ, while TEM shows that LL-37 inhibits Aβ42 fibril formation, particularlyAβ's ability to form long, straight fibrils characteristic of AD.CDreveals that LL-37 preventsAβ42 from adopting its typical β-type secondary structure. Microglia-mediated toxicities of LL-37 and Aβ42 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 Aβ42 may be natural binding partners, which implies that balanced (or unbalanced) spatiotemporal expression of the two peptides could impact AD initiation and progression.

Original languageEnglish
Pages (from-to)1213-1226
Number of pages14
JournalJournal of Alzheimer's Disease
Volume59
Issue number4
DOIs
Publication statusPublished - 2017

Fingerprint

Amyloid
Alzheimer Disease
Peptides
Surface Plasmon Resonance
Microglia
Transmission Electron Microscopy
Aptitude
Capillary Electrophoresis
Circular Dichroism
Neuroblastoma
Disease Progression
Spectrum Analysis
Neurons
Cell Line
CAP18 lipopolysaccharide-binding protein

Keywords

  • Alzheimer's disease
  • amyloid-β peptide
  • cathelicidin
  • innate immunity
  • LL-37
  • microglia

ASJC Scopus subject areas

  • Clinical Psychology
  • Geriatrics and Gerontology
  • Psychiatry and Mental health

Cite this

Evidence that the human innate immune peptide LL-37 may be a binding partner of amyloid-β and inhibitor of fibril assembly. / De Lorenzi, Ersilia; Chiari, Marcella; Colombo, Raffaella; Cretich, Marina; Sola, Laura; Vanna, Renzo; Gagni, Paola; Bisceglia, Federica; Morasso, Carlo; Lin, Jennifer S.; Lee, Moonhee; Mcgeer, Patrick L.; Barron, Annelise E.

In: Journal of Alzheimer's Disease, Vol. 59, No. 4, 2017, p. 1213-1226.

Research output: Contribution to journalArticle

De Lorenzi, E, Chiari, M, Colombo, R, Cretich, M, Sola, L, Vanna, R, Gagni, P, Bisceglia, F, Morasso, C, Lin, JS, Lee, M, Mcgeer, PL & Barron, AE 2017, 'Evidence that the human innate immune peptide LL-37 may be a binding partner of amyloid-β and inhibitor of fibril assembly', Journal of Alzheimer's Disease, vol. 59, no. 4, pp. 1213-1226. https://doi.org/10.3233/JAD-170223
De Lorenzi, Ersilia ; Chiari, Marcella ; Colombo, Raffaella ; Cretich, Marina ; Sola, Laura ; Vanna, Renzo ; Gagni, Paola ; Bisceglia, Federica ; Morasso, Carlo ; Lin, Jennifer S. ; Lee, Moonhee ; Mcgeer, Patrick L. ; Barron, Annelise E. / Evidence that the human innate immune peptide LL-37 may be a binding partner of amyloid-β and inhibitor of fibril assembly. In: Journal of Alzheimer's Disease. 2017 ; Vol. 59, No. 4. pp. 1213-1226.
@article{876fd3fa0f9f43e6b84f8ea0637a202d,
title = "Evidence that the human innate immune peptide LL-37 may be a binding partner of amyloid-β and inhibitor of fibril assembly",
abstract = "Background: Identifying physiologically relevant binding partners of amyloid-β (Aβ) 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 Aβ42 and can modulate Aβ fibril formation. Methods: Specific interactions between LL-37 and Aβ (with Aβ 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,Aβ42 alone, and LL-37/Aβ complexes were evaluated in human microglia and neuroblastoma cell lines (SH-SY5Y). Results: SPRi shows binding specificity between LL-37 and Aβ, while TEM shows that LL-37 inhibits Aβ42 fibril formation, particularlyAβ's ability to form long, straight fibrils characteristic of AD.CDreveals that LL-37 preventsAβ42 from adopting its typical β-type secondary structure. Microglia-mediated toxicities of LL-37 and Aβ42 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 Aβ42 may be natural binding partners, which implies that balanced (or unbalanced) spatiotemporal expression of the two peptides could impact AD initiation and progression.",
keywords = "Alzheimer's disease, amyloid-β peptide, cathelicidin, innate immunity, LL-37, microglia",
author = "{De Lorenzi}, Ersilia and Marcella Chiari and Raffaella Colombo and Marina Cretich and Laura Sola and Renzo Vanna and Paola Gagni and Federica Bisceglia and Carlo Morasso and Lin, {Jennifer S.} and Moonhee Lee and Mcgeer, {Patrick L.} and Barron, {Annelise E.}",
year = "2017",
doi = "10.3233/JAD-170223",
language = "English",
volume = "59",
pages = "1213--1226",
journal = "Journal of Alzheimer's Disease",
issn = "1387-2877",
publisher = "IOS Press",
number = "4",

}

TY - JOUR

T1 - Evidence that the human innate immune peptide LL-37 may be a binding partner of amyloid-β and inhibitor of fibril assembly

AU - De Lorenzi, Ersilia

AU - Chiari, Marcella

AU - Colombo, Raffaella

AU - Cretich, Marina

AU - Sola, Laura

AU - Vanna, Renzo

AU - Gagni, Paola

AU - Bisceglia, Federica

AU - Morasso, Carlo

AU - Lin, Jennifer S.

AU - Lee, Moonhee

AU - Mcgeer, Patrick L.

AU - Barron, Annelise E.

PY - 2017

Y1 - 2017

N2 - Background: Identifying physiologically relevant binding partners of amyloid-β (Aβ) 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 Aβ42 and can modulate Aβ fibril formation. Methods: Specific interactions between LL-37 and Aβ (with Aβ 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,Aβ42 alone, and LL-37/Aβ complexes were evaluated in human microglia and neuroblastoma cell lines (SH-SY5Y). Results: SPRi shows binding specificity between LL-37 and Aβ, while TEM shows that LL-37 inhibits Aβ42 fibril formation, particularlyAβ's ability to form long, straight fibrils characteristic of AD.CDreveals that LL-37 preventsAβ42 from adopting its typical β-type secondary structure. Microglia-mediated toxicities of LL-37 and Aβ42 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 Aβ42 may be natural binding partners, which implies that balanced (or unbalanced) spatiotemporal expression of the two peptides could impact AD initiation and progression.

AB - Background: Identifying physiologically relevant binding partners of amyloid-β (Aβ) 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 Aβ42 and can modulate Aβ fibril formation. Methods: Specific interactions between LL-37 and Aβ (with Aβ 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,Aβ42 alone, and LL-37/Aβ complexes were evaluated in human microglia and neuroblastoma cell lines (SH-SY5Y). Results: SPRi shows binding specificity between LL-37 and Aβ, while TEM shows that LL-37 inhibits Aβ42 fibril formation, particularlyAβ's ability to form long, straight fibrils characteristic of AD.CDreveals that LL-37 preventsAβ42 from adopting its typical β-type secondary structure. Microglia-mediated toxicities of LL-37 and Aβ42 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 Aβ42 may be natural binding partners, which implies that balanced (or unbalanced) spatiotemporal expression of the two peptides could impact AD initiation and progression.

KW - Alzheimer's disease

KW - amyloid-β peptide

KW - cathelicidin

KW - innate immunity

KW - LL-37

KW - microglia

UR - http://www.scopus.com/inward/record.url?scp=85027534082&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85027534082&partnerID=8YFLogxK

U2 - 10.3233/JAD-170223

DO - 10.3233/JAD-170223

M3 - Article

AN - SCOPUS:85027534082

VL - 59

SP - 1213

EP - 1226

JO - Journal of Alzheimer's Disease

JF - Journal of Alzheimer's Disease

SN - 1387-2877

IS - 4

ER -