Amyloid-β-Induced Ion Flux in Artificial Lipid Bilayers and Neuronal Cells: Resolving a Controversy

Capone, Ricardo; Quiroz, Felipe García; Prangkio, Panchika; Saluja, Inderjeet; Sauer, Anna; Bautista, Matthew; Turner, R. Scott; Yang, Jerry; Mayer, Michael

doi:10.1007/s12640-009-9033-1

Cited by 99 publications

(126 citation statements)

References 111 publications

Supporting

Mentioning

119

Contrasting

Order By: Relevance

“…However, this mechanism has been challenged. Capone et al (62) proposed that the membrane thinning was due to the residual solvent (hexafluoroisopropanol) used during A␤ oligomer preparation and was independent of the peptide itself.…”

Section: Actions Of A␤ On Endogenous Plasmalemmal Ion Channels-mentioning

confidence: 99%

Calcium Signaling and Amyloid Toxicity in Alzheimer Disease

Demuro

Parker

Stutzmann

2010

Journal of Biological Chemistry

354

315

View full text Add to dashboard Cite

Section: Actions Of A␤ On Endogenous Plasmalemmal Ion Channels-mentioning

confidence: 99%

Calcium Signaling and Amyloid Toxicity in Alzheimer Disease

Demuro

Parker

Stutzmann

2010

Journal of Biological Chemistry

354

315

View full text Add to dashboard Cite

“…Images were acquired with a Multimode AFM, using a Nanoscope IVA controller (Veeco). Single-channel conductance measurements were carried out using painted membranes as published previously (8,13,14,(46)(47)(48)(49) (SI Materials and Methods). Cell (APP-deficient mouse fibroblast cell line) calcium imaging (Fluo-4 NW) was carried out for p3 and N9 (under normal and reduced extracellular calcium levels, as well as with and without preincubation with zinc chloride), p3-F19P mutant, and scrambled p3 peptides under normal extracellular calcium level.…”

mentioning

confidence: 99%

Truncated β-amyloid peptide channels provide an alternative mechanism for Alzheimer’s Disease and Down syndrome

Jang

Arce

Ramachandran

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

Self Cite

211

334

View full text Add to dashboard Cite

Full-length amyloid beta peptides (Aβ 1-40/42 ) form neuritic amyloid plaques in Alzheimer's disease (AD) patients and are implicated in AD pathology. However, recent transgenic animal models cast doubt on their direct role in AD pathology. Nonamyloidogenic truncated amyloid-beta fragments and Aβ ) are also found in amyloid plaques of AD and in the preamyloid lesions of Down syndrome, a model system for early-onset AD study. Very little is known about the structure and activity of these smaller peptides, although they could be the primary AD and Down syndrome pathological agents. Using complementary techniques of molecular dynamics simulations, atomic force microscopy, channel conductance measurements, calcium imaging, neuritic degeneration, and cell death assays, we show that nonamyloidogenic Aβ 9-42 and Aβ 17-42 peptides form ion channels with loosely attached subunits and elicit single-channel conductances. The subunits appear mobile, suggesting insertion of small oligomers, followed by dynamic channel assembly and dissociation. These channels allow calcium uptake in amyloid precursor protein-deficient cells. The channel mediated calcium uptake induces neurite degeneration in human cortical neurons. Channel conductance, calcium uptake, and neurite degeneration are selectively inhibited by zinc, a blocker of amyloid ion channel activity. Thus, truncated Aβ fragments could account for undefined roles played by full length Aβs and provide a unique mechanism of AD and Down syndrome pathologies. The toxicity of nonamyloidogenic peptides via an ion channel mechanism necessitates a reevaluation of the current therapeutic approaches targeting the nonamyloidogenic pathway as avenue for AD treatment.atomic force microscopy | molecular dynamics | cell calcium imaging | neurite degeneration and cell death assays | single-channel conductance A myloid-beta peptides (Aβ 1-40/42 ) produced by β-and γ-secretase processing of amyloid precursor protein (APP) in the amyloidogenic pathway are involved in Alzheimer's disease (AD) pathology. Aβ 1-40/42 peptides form β-sheet-rich ordered aggregates and soluble oligomers. Small oligomers are emerging as the predominant toxic species (1-3); the toxicity is believed to be a result of the loss of ionic homeostasis, presumably via ion channels formed in cellular membranes (4, 5). EM images of Aβ oligomers show doughnut-like morphologies (6). Atomic force microscopic (AFM) images of Aβ peptides reconstituted in lipid bilayers show heteromeric (rectangular to hexagonal) ion channel-like structures with a ∼2.0-nm central pore and 8-to 12-nm outer diameters (7,8). Electrophysiological studies show heterodisperse cationselective single-channel conductances (7)(8)(9)(10)(11)(12)(13)(14) that are consistent with features of other amyloid ion channels (6-8).On the other hand, when APP is cleaved by γ-and α-secretases, it forms the nonamyloidogenic pathway generating ∼2.6-kDa fragments (Aβ 17-40/42 ) known as the p3 peptides (15). Cleavage by γ and BACE between Tyr10 and Glu11 generates another...

show abstract

“…Cholesterol has been shown to be involved in the regulation of ion channels and Aβ has been shown to closely regulate various ion channels [139][140][141][142]. In particular, Aβ oligomer formation is cytotoxic and leads to neuronal death with alterations in membrane ion channel activity and synaptic plasticity [143,144]. The role of specific phytosterols in the brain and their effects on the regulation of cholesterol and ion channels are poorly understood and diets that contain specific phytosterols and their relationship to Aβ and ion channels may have important implications for aging and AD.…”

Section: Phytosterols and Cholesterol Homeostasismentioning

confidence: 99%