Fresh and globular amyloid β protein (1–42) induces rapid cellular degeneration: evidence for AβP channel‐mediated cellular toxicity

Bhatia, Rajinder; Lin, Hai; Lal, R.

doi:10.1096/fasebj.14.9.1233

Cited by 224 publications

(201 citation statements)

References 57 publications

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“…The second type includes oligomers of 25-40-mers size; their binding to amyloid specific dyes thioflavine T and Congo red and the development of far UV CD spectrum similar to the fibrillar CD signal indicate the formation of cross-b-sheet structure. Both types of oligomers exhibit similar roundshaped morphology in AFM images which is commonly associated with prefibrillar amyloid [1][2][3][4][5]. Here we have demonstrated that only the second enlarged type of oligomers produce cytotoxic effect on two kinds of neuronal cells.…”

Section: Discussionsupporting

confidence: 60%

“…However the definition of the toxic amyloid species and their particular structural properties exerting the specific cytotoxic effect remain controversial. In the last years a number of studies have supported the hypothesis that early aggregates or prefibrillar species are implicated in cytotoxicity while fibrillar amyloid deposits serve as an escape route for smaller aggregates [1][2][3][4][5]. Among them Kayed et al observed that intermediate-size water soluble oligomers of Ab and other five proteins form sheared structures characterized by similar conformational epitope, suggesting that they exert cytotoxicity via similar mechanisms [6].…”

Section: Introductionmentioning

confidence: 99%

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Cytotoxicity of albebetin oligomers depends on cross‐β‐sheet formation

et al. 2006

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Prefibrillar cytotoxicity was suggested as a common amyloid characteristic. We showed two types of albebetin prefibrillar oligomers are formed during incubation at pH 7.3. Initial round-shaped oligomers consist of 10-15 molecules determined by atomic force microscopy, do not bind thioflavin-T and do not affect viability of granular neurons and SH-SY5Y cells. They are converted into ca. 30-40-mers possessing cross-b-sheet and reducing viability of neuronal cells. Neither monomers nor fibrils possess cytotoxicity. We suggest that oligomeric size is important for stabilising cross-b-sheet core critical for cytotoxicity. As albebetin was used as a carrier-protein for drug delivery, examination of amyloidogenicity is required prior polypeptide biomedical applications.

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Section: Discussionsupporting

confidence: 60%

Section: Introductionmentioning

confidence: 99%

Cytotoxicity of albebetin oligomers depends on cross‐β‐sheet formation

et al. 2006

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“…It is thus of great interest to elucidate the physiological role of Ah under normal conditions. At present, the physiological role of Ah is not clear, but suggestions include a neurotrophic action at a low concentration (Chauhan et al, 1991), enhancement of N-methyl-D-aspartate (NMDA) receptormediated current (Furukawa and Mattson, 1998;Harkany et al, 2000) and long-term potentiation (Ishida et al, 1997), enhancement of AMPA receptor-mediated current (Blanchard et al, 1997), formation of calcium channels (Bhatia et al, 2000), and effects on intracellular calcium homeostasis (Bhatia et al, 2000;Mattson et al, 1993). Most of these suggestions need to be confirmed, and it is not clear whether the suggested actions of Ah can be mediated by physiological concentrations of Ah.…”

Section: Discussionmentioning

confidence: 99%

Amyloid beta peptide directly inhibits PKC activation

Lee

Boo

Jung

et al. 2004

Molecular and Cellular Neuroscience

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“…The target of the A␤ peptide in biological and model membranes is phosphatidylserine (PS), the proapoptic signaling phospholipid (37). Subsequently the calcium channel properties of A␤ have been verified in many other laboratories (38)(39)(40)(41)(42). We and others have therefore hypothesized that calcium conducted into the target neurons by the A␤ channel might be responsible for A␤ neurotoxicity.…”

mentioning

confidence: 82%

Small molecule blockers of the Alzheimer Aβ calcium channel potently protect neurons from Aβ cytotoxicity

Díaz

Šimáková

Jacobson

et al. 2009

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

107

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Alzheimer's disease (AD) is a common, chronic neurodegenerative disease that is thought to be caused by the neurotoxic effect of the Amyloid beta peptides (A␤). We have hypothesized that the intrinsic A␤ calcium channel activity of the oligomeric A␤ polymer may be responsible for the neurotoxic properties of A␤, and that A␤ channel blockers may be candidate AD therapeutics. As a consequence of a rational search paradigm based on the model structure of the A␤ channel, we have identified two compounds of interest: MRS2481 and an enatiomeric species, MRS2485. These are amphiphilic pyridinium salts that both potently block the A␤ channel and protect neurons from A␤ toxicity. Both block the A␤ channel with similar potency (Ϸ500 nM) and efficacy (100%). However, we find that inhibition by MRS2481 is easily reversible, whereas inhibition by MRS2485 is virtually irreversible. We suggest that both species deserve consideration as candidates for Alzheimer's disease drug discovery.brain ͉ neurodegeneration ͉ rational drug design ͉ drug ͉ toxicity A lzheimer's disease (AD) is a chronic neurodegenerative disease characterized behaviorally by progressive memory loss, and neuronal degeneration in the cerebral cortex, hippocampus, and elsewhere (1, 2). The neuropathology of AD is characterized by amyloid plaques and neuro-fibrillary tangles. The amyloid plaque material has been found to be composed principally of a 40Ϫ42-residue peptide, called amyloid ␤-peptide, or ''A␤'' (3). Both forms of A␤40/42 have been found to be kill neurons and certain other cells in culture. Altogether, these findings have provided strong support for the hypothesis that AD is due to neurotoxic effects of A␤ on susceptible neurons (4-10).The mechanism of A␤ neurotoxicity has been pursued for decades in hopes of translating such knowledge into a pharmaceutical therapy for AD. Cholinesterase inhibitors were the first generation of such candidate therapeutics (11-15). A second generation of candidate therapeutics has included a series of attempts to inhibit the formation of amyloid plaques. Active (16-23) and passive (24) immunization approaches are presently being tested. However, some patients in the active human immunization trials have developed meningoencephalitis (25,26). Yet another alternative has been to reduce the levels of A␤ in the brain by inhibiting the proteolytic enzymes associated with trimming APP into A␤ 40 or 42 (27-31).An entirely different approach to the mechanism of A␤ neurotoxicity has been developed following the observation that oligomers of A␤ peptides themselves formed calcium conducting channels in bilayer membranes in vitro (32)(33)(34)(35), and in intact neurons (36). The target of the A␤ peptide in biological and model membranes is phosphatidylserine (PS), the proapoptic signaling phospholipid (37). Subsequently the calcium channel properties of A␤ have been verified in many other laboratories (38-42). We and others have therefore hypothesized that calcium conducted into the target neurons by the A␤ channel might be respo...

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Fresh and globular amyloid β protein (1–42) induces rapid cellular degeneration: evidence for AβP channel‐mediated cellular toxicity

Cited by 224 publications

References 57 publications

Cytotoxicity of albebetin oligomers depends on cross‐β‐sheet formation

Cytotoxicity of albebetin oligomers depends on cross‐β‐sheet formation

Amyloid beta peptide directly inhibits PKC activation

Small molecule blockers of the Alzheimer Aβ calcium channel potently protect neurons from Aβ cytotoxicity

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