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Observation of β‑Amyloid Peptide Oligomerization by Pressure-Jump NMR Spectroscopy
journal contribution
posted on 2019-08-23, 19:03 authored by C. Ashley Barnes, Angus J. Robertson, John M. Louis, Philip Anfinrud, Ad BaxBrain tissue of Alzheimer’s
disease patients invariably
contains deposits of insoluble, fibrillar aggregates of peptide fragments
of the amyloid precursor protein (APP), typically 40 or 42 residues
in length and referred to as Aβ40 and Aβ42. However, it remains unclear whether these fibrils or oligomers
constitute the toxic species. Depending on sample conditions, oligomers
can form in a few seconds or less. These oligomers are invisible to
solution NMR spectroscopy, but they can be rapidly (<1 s) resolubilized
and converted to their NMR-visible monomeric constituents by raising
the hydrostatic pressure to a few kbar. Hence, utilizing pressure-jump
NMR, the oligomeric state can be studied at residue-specific resolution
by monitoring its signals in the monomeric state. Oligomeric states
of Aβ40 exhibit a high degree of order, reflected
by slow longitudinal 15N relaxation (T1 > 5 s) for residues 18–21 and 31–34,
whereas
the N-terminal 10 residues relax much faster (T1 ≤ 1.5 s), indicative of extensive internal motions.
Transverse relaxation rates rapidly increase to ca. 1000 s–1 after the oligomerization is initiated.
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fibrillar aggregatesamyloid precursor proteinPressure-Jump NMR Spectroscopy Brain tissuepeptide fragmentsβ 40 exhibitβ 42β 40APPT 1oligomeric statesample conditionsTransverse relaxation ratesNMR-visible monomeric constituents15 N relaxationN-terminal 10 residuesOligomeric states42 residuessolution NMR spectroscopypressure-jump NMRmonomeric stateresidue-specific resolution
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