Format

Send to

Choose Destination
See comment in PubMed Commons below
J Cell Biol. 2011 Oct 31;195(3):515-24. doi: 10.1083/jcb.201104133. Epub 2011 Oct 24.

Single-channel Ca(2+) imaging implicates Aβ1-42 amyloid pores in Alzheimer's disease pathology.

Author information

1
Department of Neurobiology and Behavior, University of California, Irvine, Irvine, CA 92697, USA. ademuro@uci.edu

Abstract

Oligomeric forms of Aβ peptides are implicated in Alzheimer's disease (AD) and disrupt membrane integrity, leading to cytosolic calcium (Ca(2+)) elevation. Proposed mechanisms by which Aβ mediates its effects include lipid destabilization, activation of native membrane channels, and aggregation of Aβ into Ca(2+)-permeable pores. We distinguished between these using total internal reflection fluorescence (TIRF) microscopy to image Ca(2+) influx in Xenopus laevis oocytes. Aβ1-42 oligomers evoked single-channel Ca(2+) fluorescence transients (SCCaFTs), which resembled those from classical ion channels but which were not attributable to endogenous oocyte channels. SCCaFTs displayed widely variable open probabilities (P(o)) and stepwise transitions among multiple amplitude levels reminiscent of subconductance levels of ion channels. The proportion of high P(o), large amplitude SCCaFTs grew with time, suggesting that continued oligomer aggregation results in the formation of highly toxic pores. We conclude that formation of intrinsic Ca(2+)-permeable membrane pores is a major pathological mechanism in AD and introduce TIRF imaging for massively parallel single-channel studies of the incorporation, assembly, and properties of amyloidogenic oligomers.

PMID:
22024165
PMCID:
PMC3206345
DOI:
10.1083/jcb.201104133
[Indexed for MEDLINE]
Free PMC Article
PubMed Commons home

PubMed Commons

0 comments
How to join PubMed Commons

    Supplemental Content

    Full text links

    Icon for HighWire Icon for PubMed Central
    Loading ...
    Support Center