Unique molecular signatures of Alzheimer's disease amyloid β peptide mutations and deletion during aggregate/oligomer/fibril formation

Joseph F. Poduslo, Kyle G. Howell

Research output: Contribution to journalArticle

5 Citations (Scopus)

Abstract

The formation of amyloid β (Aβ) peptide aggregates, oligomers, and fibrils is a dynamic process; however, the kinetics of their formation is not well understood. This study compares the time course of aggregate/fibril formation by transmission electron microscopy (TEM) analyses with that of oligomer/fibril formation by Western blot analysis under native and denaturing conditions. Efforts to deaggregate/defibrillate these peptides by using hexafluoroisopropanol, ammonium hydroxide, or dimethylsulfoxide did not change the nondenaturing polyacrylamide gel electrophoresis (PAGE) footprints or drive the peptides to a monomeric species. Regardless of the pretreatment protocol, TEM analyses reveal that all Aβ peptides (Aβ40, Aβ42, Aβ39E22Δ [Osaka], Aβ40E22G [Arctic], Aβ40E22Q [Dutch], and Aβ40A2T [Icelandic]) immediately formed nonfibrillar, amorphous aggregates when first placed into solution with the Osaka mutation, quickly forming early-stage fibrils. The extent of fibril formation for other Aβ peptides is time dependent, with the Arctic mutation forming fibrils at 1 hr, the Dutch and Icelandic at 4 hr, Aβ42 at 8 hr, and Aβ40 at 24 hr. In contrast, nondenaturing PAGE revealed unique footprints for the different Aβ species. The rapidity of aggregate formation and the rapid transition to fibrils, particularly for the Osaka deletion, suggest an important role for aggregates/fibrils of Aβ in the development of neuronal degeneration.

Original languageEnglish (US)
Pages (from-to)410-423
Number of pages14
JournalJournal of Neuroscience Research
Volume93
Issue number3
DOIs
StatePublished - Mar 1 2015

Fingerprint

Sequence Deletion
Amyloid
Alzheimer Disease
Peptides
Transmission Electron Microscopy
Polyacrylamide Gel Electrophoresis
Ammonium Hydroxide
Mutation
Dimethyl Sulfoxide
Western Blotting

Keywords

  • Amyloid fibrils
  • Protein aggregation
  • Protein oligomers

ASJC Scopus subject areas

  • Cellular and Molecular Neuroscience

Cite this

Unique molecular signatures of Alzheimer's disease amyloid β peptide mutations and deletion during aggregate/oligomer/fibril formation. / Poduslo, Joseph F.; Howell, Kyle G.

In: Journal of Neuroscience Research, Vol. 93, No. 3, 01.03.2015, p. 410-423.

Research output: Contribution to journalArticle

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