Autocatalytic amplification of Alzheimer-associated Aβ42 peptide aggregation in human cerebrospinal fluid

Alzheimer’s disease is linked to amyloid β (Aβ) peptide aggregation in the brain, and a detailed understanding of the molecular mechanism of Aβ aggregation may lead to improved diagnostics and therapeutics. While previous studies have been performed in pure buffer, we approach the mechanism in vivo using cerebrospinal fluid (CSF). We investigated the aggregation mechanism of Aβ42 in human CSF through kinetic experiments at several Aβ42 monomer concentrations (0.8–10 µM). The data were subjected to global kinetic analysis and found consistent with an aggregation mechanism involving secondary nucleation of monomers on the fibril surface. A mechanism only including primary nucleation was ruled out. We find that the aggregation process is composed of the same microscopic steps in CSF as in pure buffer, but the rate constant of secondary nucleation is decreased. Most importantly, the autocatalytic amplification of aggregate number through catalysis on the fibril surface is prevalent also in CSF.Rebecca Frankel, Mattias Törnquist et al. report the aggregation mechanism of Aβ42 in human cerebrospinal fluid in vitro. They find evidence consistent with an aggregation mechanism involving secondary nucleation of monomers on the fibril surface.

[1]  Sara Linse,et al.  Atomic Resolution Structure of Monomorphic Aβ42 Amyloid Fibrils. , 2016, Journal of the American Chemical Society.

[2]  Sara Linse,et al.  Amyloid β-protein aggregation produces highly reproducible kinetic data and occurs by a two-phase process. , 2010, ACS chemical neuroscience.

[3]  B. Winblad,et al.  A pathogenic mutation for probable Alzheimer's disease in the APP gene at the N–terminus of β–amyloid , 1992, Nature Genetics.

[4]  Tuomas P. J. Knowles,et al.  Systematic development of small molecules to inhibit specific microscopic steps of Aβ42 aggregation in Alzheimer’s disease , 2016, Proceedings of the National Academy of Sciences.

[5]  Alexander K. Buell,et al.  Distinct thermodynamic signature of oligomer generation in the aggregation of the amyloid-β peptide , 2018, Nature Chemistry.

[6]  Shaomin Li,et al.  Secreted Amyloid β-Proteins in a Cell Culture Model Include N-Terminally Extended Peptides That Impair Synaptic Plasticity , 2014, Biochemistry.

[7]  Tuomas P. J. Knowles,et al.  Quantitative analysis of intrinsic and extrinsic factors in the aggregation mechanism of Alzheimer-associated Aβ-peptide , 2016, Scientific Reports.

[8]  J. Allen.  Human Physiology - the Basis of Medicine , 2008, The Ulster Medical Journal.

[9]  W. K. Cullen,et al.  Naturally secreted oligomers of amyloid β protein potently inhibit hippocampal long-term potentiation in vivo , 2002, Nature.

[10]  S. Linse,et al.  Secondary nucleation in amyloid formation. , 2018, Chemical communications.

[11]  Sara Linse,et al.  A facile method for expression and purification of the Alzheimer’s disease-associated amyloid β-peptide , 2009, The FEBS journal.

[12]  K. Blennow,et al.  Amyloid biomarkers in Alzheimer's disease. , 2015, Trends in pharmacological sciences.

[13]  John Hardy,et al.  The amyloid hypothesis for Alzheimer’s disease: a critical reappraisal , 2009, Journal of neurochemistry.

[14]  S. Younkin,et al.  The 'Arctic' APP mutation (E693G) causes Alzheimer's disease by enhanced Aβ protofibril formation , 2001, Nature Neuroscience.

[15]  M. Delgado-Rodríguez,et al.  Systematic review and meta-analysis. , 2017, Medicina intensiva.

[16]  C. Dobson,et al.  Modulation of electrostatic interactions to reveal a reaction network unifying the aggregation behaviour of the Aβ42 peptide and its variants† †Electronic supplementary information (ESI) available. See DOI: 10.1039/c7sc00215g Click here for additional data file. , 2017, Chemical science.

[17]  K. Blennow,et al.  Alzheimer's disease , 2016, The Lancet.

[18]  A. Fagan,et al.  ApoE4 markedly exacerbates tau-mediated neurodegeneration in a mouse model of tauopathy , 2017, Nature.

[19]  J. Gilbert,et al.  Early-Onset Alzheimer Disease and Candidate Risk Genes Involved in Endolysosomal Transport , 2017, JAMA neurology.

[20]  Christopher D. Richards,et al.  Human Physiology, The Basis of Medicine , 1999 .

[21]  W. M. van der Flier,et al.  Characterization of pathogenic SORL1 genetic variants for association with Alzheimer’s disease: a clinical interpretation strategy , 2017, European Journal of Human Genetics.

[22]  K. Blennow,et al.  CSF and blood biomarkers for the diagnosis of Alzheimer's disease: a systematic review and meta-analysis , 2016, The Lancet Neurology.

[23]  Michele Vendruscolo,et al.  An anticancer drug suppresses the primary nucleation reaction that initiates the production of the toxic Aβ42 aggregates linked with Alzheimer’s disease , 2016, Science Advances.

[24]  J. Hardy,et al.  Early-onset Alzheimer's disease caused by mutations at codon 717 of the β-amyloid precursor protein gene , 1991, Nature.

[25]  G. Glenner,et al.  Alzheimer's disease: initial report of the purification and characterization of a novel cerebrovascular amyloid protein. , 1984, Biochemical and biophysical research communications.

[26]  Michael Ruse,et al.  Mechanisms and Models , 2007 .

[27]  Tuomas P. J. Knowles,et al.  On the lag phase in amyloid fibril formation , 2015, Physical chemistry chemical physics : PCCP.

[28]  J. Hardy,et al.  Amyloid deposition as the central event in the aetiology of Alzheimer's disease. , 1991, Trends in pharmacological sciences.

[29]  Michele Vendruscolo,et al.  Proliferation of amyloid-β42 aggregates occurs through a secondary nucleation mechanism , 2013, Proceedings of the National Academy of Sciences.

[30]  K. Beyreuther,et al.  A4 Protein in Alzheimer's Disease: Primary and Secondary Cellular Events in Extracellular Amyloid Deposition , 1989, Journal of neuropathology and experimental neurology.

[31]  H. Wiśniewski,et al.  Effect of cerebrospinal fluid from normal and Alzheimer's patients with different apolipoprotein E phenotypes on in vitro aggregation of amyloid beta-protein , 1996, Journal of the Neurological Sciences.

[32]  A. Paterson,et al.  Secondary Nucleation: Mechanisms and Models , 2015 .

[33]  J. Hardy,et al.  Alzheimer's disease: the amyloid cascade hypothesis. , 1992, Science.

[34]  M. M. Bradford.  A rapid and sensitive method for the quantitation of microgram quantities of protein utilizing the principle of protein-dye binding. , 1976, Analytical biochemistry.

[35]  Claudia Manzoni,et al.  A Recessive Mutation in the APP Gene with Dominant-Negative Effect on Amyloidogenesis , 2009, Science.

[36]  D. Selkoe,et al.  The therapeutics of Alzheimer's disease: Where we stand and where we are heading , 2013, Annals of neurology.

[37]  J. Danielsson,et al.  Ionic Strength Modulation of the Free Energy Landscape of Aβ40 Peptide Fibril Formation. , 2016, Journal of the American Chemical Society.

[38]  Peter Güntert,et al.  Atomic-resolution structure of a disease-relevant Aβ(1–42) amyloid fibril , 2016, Proceedings of the National Academy of Sciences.

[39]  L. Bilston,et al.  Effects of Proteins, Blood Cells and Glucose on the Viscosity of Cerebrospinal Fluid , 1998, Pediatric Neurosurgery.

[40]  A. Šarić,et al.  Scaling behaviour and rate-determining steps in filamentous self-assembly† †Electronic supplementary information (ESI) available. See DOI: 10.1039/c7sc01965c Click here for additional data file. , 2017, Chemical science.

[41]  J. Weuve,et al.  Alzheimer disease in the United States (2010–2050) estimated using the 2010 census , 2013, Neurology.

[42]  S. Linse,et al.  On the role of sidechain size and charge in the aggregation of Aβ42 with familial mutations , 2018, Proceedings of the National Academy of Sciences.

[43]  Michele Vendruscolo,et al.  The molecular chaperone Brichos breaks the catalytic cycle that generates toxic Aβ oligomers , 2015, Nature Structural &Molecular Biology.

[44]  B. Ghetti,et al.  A mutation in the amyloid precursor protein associated with hereditary Alzheimer's disease. , 1991, Science.

[45]  R. Martins,et al.  Amyloid A4 protein and its precursor in Down's syndrome and Alzheimer's disease. , 1989, The New England journal of medicine.

[46]  J. Levin,et al.  RIPK1 mediates a disease-associated microglial response in Alzheimer’s disease , 2017, Proceedings of the National Academy of Sciences.

[47]  Anders Wallin,et al.  An Alzheimer's disease-specific β-amyloid fragment signature in cerebrospinal fluid , 2006, Neuroscience Letters.

[48]  Koichi Tanaka,et al.  Identification and quantification of amyloid beta-related peptides in human plasma using matrix-assisted laser desorption/ionization time-of-flight mass spectrometry , 2014, Proceedings of the Japan Academy. Series B, Physical and biological sciences.

[49]  Michael T. Colvin,et al.  N-Terminal Extensions Retard Aβ42 Fibril Formation but Allow Cross-Seeding and Coaggregation with Aβ42. , 2015, Journal of the American Chemical Society.

[50]  G. Botsaris.  Secondary Nucleation — A Review , 1976 .

[51]  A. Korczyn.  The amyloid cascade hypothesis , 2008, Alzheimer's & Dementia.

[52]  D. Selkoe.  Alzheimer's disease. , 2011, Cold Spring Harbor perspectives in biology.

[53]  G. Glenner,et al.  Alzheimer's disease: Initial report of the purification and characterization of a novel cerebrovascular amyloid protein , 1984 .

[54]  T. Wisniewski,et al.  Cerebrospinal fluid inhibits Alzheimer β‐amyloid fibril formation in vitro , 1993, Annals of neurology.

[55]  E. Head,et al.  Down syndrome and beta-amyloid deposition , 2004, Current opinion in neurology.

[56]  C. Masters,et al.  Amyloid plaque core protein in Alzheimer disease and Down syndrome. , 1985, Proceedings of the National Academy of Sciences of the United States of America.

[57]  S. Linse.  Monomer-dependent secondary nucleation in amyloid formation , 2017, Biophysical Reviews.

[58]  Sara Linse,et al.  Differences in nucleation behavior underlie the contrasting aggregation kinetics of the Aβ40 and Aβ42 peptides , 2014, Proceedings of the National Academy of Sciences.

[59]  J. Borén,et al.  Cerebrospinal fluid-induced retardation of amyloid β aggregation correlates with Alzheimer's disease and the APOE ε4 allele , 2016, Brain Research.

[60]  Michele Vendruscolo,et al.  Molecular mechanisms of protein aggregation from global fitting of kinetic models , 2016, Nature Protocols.