Ordered and Disordered Segments of Amyloid-β Drive Sequential Steps of the Toxic Pathway

Barun Kumar Maity, Anand Kant Das, Simli Dey, Ullhas Kaarthi Moorthi, Amandeep Kaur, Arpan Dey, Dayana Surendran, Rucha Pandit, Mamata Kallianpur, Bappaditya Chandra, Muralidharan Chandrakesan, Senthil Arumugam, Sudipta Maiti

Research output: Contribution to journalArticleResearchpeer-review

Abstract

While the roles of intrinsically disordered protein domains in driving interprotein interactions are increasingly well-appreciated, the mechanism of toxicity of disease-causing disordered proteins remains poorly understood. A prime example is Alzheimer's disease (AD) associated amyloid beta (Aβ). Aβ oligomers are highly toxic partially structured peptide assemblies with a distinct ordered region (residues 10-40) and a shorter disordered region (residues 1-9). Here, we investigate the role of this disordered domain and its relation to the ordered domain in the manifestation of toxicity through a set of Aβ fragments and stereoisomers designed for this purpose. We measure their effects on lipid membranes and cultured neurons, probing their toxicity, intracellular distributions, and specific molecular interactions using the techniques of confocal imaging, lattice light sheet imaging, fluorescence lifetime imaging, and fluorescence correlation spectroscopy. Remarkably, we find that neither part - Aβ10-40 or Aβ1-9, is toxic by itself. The ordered part (Aβ10-40) is the major determinant of how Aβ attaches to lipid bilayers, enters neuronal cells, and localizes primarily in the late endosomal compartments. However, once Aβ enters the cell, it is the disordered part (only when it is connected to the rest of the peptide) that has a strong and stereospecific interaction with an unknown cellular component, as demonstrated by distinct changes in the fluorescence lifetime of a fluorophore attached to the N-terminal. This interaction appears to commit Aβ to the toxic pathway. Our findings correlate well with Aβ sites of familial AD mutations, a significant fraction of which cluster in the disordered region. We conclude that, while the ordered region dictates attachment and cellular entry, the key to toxicity lies in the ordered part presenting the disordered part for a specific cellular interaction.

Original languageEnglish
Pages (from-to)2498-2509
Number of pages12
JournalACS Chemical Neuroscience
Volume10
Issue number5
DOIs
Publication statusPublished - 15 May 2019
Externally publishedYes

Keywords

  • Alzheimer's disease (AD)
  • Amyloid beta fragment
  • Amyloid beta interactions
  • amyloid enantiomer
  • amyloid-membrane interaction
  • Intracellular amyloid beta

Cite this

Maity, B. K., Das, A. K., Dey, S., Moorthi, U. K., Kaur, A., Dey, A., ... Maiti, S. (2019). Ordered and Disordered Segments of Amyloid-β Drive Sequential Steps of the Toxic Pathway. ACS Chemical Neuroscience, 10(5), 2498-2509. https://doi.org/10.1021/acschemneuro.9b00015
Maity, Barun Kumar ; Das, Anand Kant ; Dey, Simli ; Moorthi, Ullhas Kaarthi ; Kaur, Amandeep ; Dey, Arpan ; Surendran, Dayana ; Pandit, Rucha ; Kallianpur, Mamata ; Chandra, Bappaditya ; Chandrakesan, Muralidharan ; Arumugam, Senthil ; Maiti, Sudipta. / Ordered and Disordered Segments of Amyloid-β Drive Sequential Steps of the Toxic Pathway. In: ACS Chemical Neuroscience. 2019 ; Vol. 10, No. 5. pp. 2498-2509.
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abstract = "While the roles of intrinsically disordered protein domains in driving interprotein interactions are increasingly well-appreciated, the mechanism of toxicity of disease-causing disordered proteins remains poorly understood. A prime example is Alzheimer's disease (AD) associated amyloid beta (Aβ). Aβ oligomers are highly toxic partially structured peptide assemblies with a distinct ordered region (residues 10-40) and a shorter disordered region (residues 1-9). Here, we investigate the role of this disordered domain and its relation to the ordered domain in the manifestation of toxicity through a set of Aβ fragments and stereoisomers designed for this purpose. We measure their effects on lipid membranes and cultured neurons, probing their toxicity, intracellular distributions, and specific molecular interactions using the techniques of confocal imaging, lattice light sheet imaging, fluorescence lifetime imaging, and fluorescence correlation spectroscopy. Remarkably, we find that neither part - Aβ10-40 or Aβ1-9, is toxic by itself. The ordered part (Aβ10-40) is the major determinant of how Aβ attaches to lipid bilayers, enters neuronal cells, and localizes primarily in the late endosomal compartments. However, once Aβ enters the cell, it is the disordered part (only when it is connected to the rest of the peptide) that has a strong and stereospecific interaction with an unknown cellular component, as demonstrated by distinct changes in the fluorescence lifetime of a fluorophore attached to the N-terminal. This interaction appears to commit Aβ to the toxic pathway. Our findings correlate well with Aβ sites of familial AD mutations, a significant fraction of which cluster in the disordered region. We conclude that, while the ordered region dictates attachment and cellular entry, the key to toxicity lies in the ordered part presenting the disordered part for a specific cellular interaction.",
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Maity, BK, Das, AK, Dey, S, Moorthi, UK, Kaur, A, Dey, A, Surendran, D, Pandit, R, Kallianpur, M, Chandra, B, Chandrakesan, M, Arumugam, S & Maiti, S 2019, 'Ordered and Disordered Segments of Amyloid-β Drive Sequential Steps of the Toxic Pathway', ACS Chemical Neuroscience, vol. 10, no. 5, pp. 2498-2509. https://doi.org/10.1021/acschemneuro.9b00015

Ordered and Disordered Segments of Amyloid-β Drive Sequential Steps of the Toxic Pathway. / Maity, Barun Kumar; Das, Anand Kant; Dey, Simli; Moorthi, Ullhas Kaarthi; Kaur, Amandeep; Dey, Arpan; Surendran, Dayana; Pandit, Rucha; Kallianpur, Mamata; Chandra, Bappaditya; Chandrakesan, Muralidharan; Arumugam, Senthil; Maiti, Sudipta.

In: ACS Chemical Neuroscience, Vol. 10, No. 5, 15.05.2019, p. 2498-2509.

Research output: Contribution to journalArticleResearchpeer-review

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T1 - Ordered and Disordered Segments of Amyloid-β Drive Sequential Steps of the Toxic Pathway

AU - Maity, Barun Kumar

AU - Das, Anand Kant

AU - Dey, Simli

AU - Moorthi, Ullhas Kaarthi

AU - Kaur, Amandeep

AU - Dey, Arpan

AU - Surendran, Dayana

AU - Pandit, Rucha

AU - Kallianpur, Mamata

AU - Chandra, Bappaditya

AU - Chandrakesan, Muralidharan

AU - Arumugam, Senthil

AU - Maiti, Sudipta

PY - 2019/5/15

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KW - amyloid enantiomer

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