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J Cell Biol. October 31, 2011; 195 (3): 515-24.

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

Demuro A , Smith M , Parker I .

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.

PubMed ID: 22024165
PMC ID: PMC3206345
Article link: J Cell Biol.
Grant support: GM48071 NIGMS NIH HHS , P50-AG16573 NIA NIH HHS , R37 GM048071 NIGMS NIH HHS , R01 GM048071 NIGMS NIH HHS , R37 GM048071 NIGMS NIH HHS , GM48071 NIGMS NIH HHS , P50 AG016573 NIA NIH HHS , P50-AG16573 NIA NIH HHS

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