Amyloid pores from pathogenic mutations

Lashuel, Hilal A.; Hartley, Dean M.; Petre, Benjamin M.; Walz, Thomas; Lansbury, Peter T.

doi:10.1038/418291a

Cited by 1,207 publications

(1,169 citation statements)

References 13 publications

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“…Our results, however, are consistent with other previous studies showing intracellular accumulation of A␤ 1-40 and A␤ 1-42 in granular deposits in late endosomes and lysosomes of human fibroblasts, PC12, monocytic and neuroblastoma cell lines [8,37,56,72]. It is increasingly recognized that disruption of the integrity of cell membranes by small prefibrillar assemblies probing into the membrane bilayer is a primary step in the induction of oxidative damage and after cell death [6,23,36,43,57,61]; the early appearance of amyloid aggregates in the cytoplasm of fibroblasts therefore suggests that these species are the main source of oxidative stress for cells. Correspondingly, we found prompt and sharp ROS production in APPV717I fibroblasts exposed to A␤ 1-40 and A␤ 1-42 aggregates.…”

Section: Discussionsupporting

confidence: 93%

Increased susceptibility to amyloid toxicity in familial Alzheimer's fibroblasts

Cecchi

Fiorillo

Baglioni

et al. 2007

Neurobiology of Aging

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Much experimental evidence suggests that an imbalance in cellular redox status is a major factor in the pathogenesis of Alzheimer's disease (AD). Our previous data showed a marked increase in membrane lipoperoxidation in primary fibroblasts from familial AD (FAD) patients. In the present study, we demonstrate that when oligomeric structures of A␤ 1-40 and A␤ 1-42 are added to the culture media, they accumulate quicker near the plasma membrane, and are internalized faster and mostly in APPV717I fibroblasts than in age-matched healthy cells; this results in an earlier and sharper increase in the production of reactive oxygen species (ROS). Higher ROS production leads in turn to an increase in membrane oxidative-injury and significant impairment of cellular antioxidant capacity, giving rise to apoptotic cascade activation and finally to a necrotic outcome. In contrast, healthy fibroblasts appear more resistant to amyloid oxidative-attack, possibly as a result of their plasma membrane integrity and powerful antioxidant capacity. Our data are consistent with increasing evidence that prefibrillar aggregates, compared to mature fibrils, are likely the more toxic species of the peptides. These findings provide compelling evidence that cells bearing increased membrane lipoperoxidation are more susceptible to aggregate toxicity as a result of their reduced ability to counteract amyloid oligomeric attack.

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Section: Discussionsupporting

confidence: 93%

Increased susceptibility to amyloid toxicity in familial Alzheimer's fibroblasts

Cecchi

Fiorillo

Baglioni

et al. 2007

Neurobiology of Aging

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“…Aggregates can also interfere with the cellular defense mechanisms by altering protein folding homeostasis (Gidalevitz et al, 2006;Satyal et al, 2000), by blocking proteasome mediated degradation (Bence et al, 2001;Bennett et al, 2005) or by inhibiting autophagy . Other models suggest that the aggregates can engage in aberrant interaction with cellular membranes leading to the formation of membrane pores (Lashuel et al, 2002) or they can disturb cellular ion homeostasis (Quist et al, 2005), may cause mitochondrial dysfunction and oxidative stress (Muller et al, 2010) (Figure 8). Neuronal cell death in diseases like Huntington's disease and Alzheimer's disease can be contributed by both loss-of-function of native active proteins and/or gain-of-function by misfolded proteins.…”

Section: Prion Protein Extracellularmentioning

confidence: 99%

Firefly luciferase mutants as sensors of proteome stress

et al. 2011

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“…In this work, we extended previous simulations to Aβ annular structures in solution since annular structures have often been observed by AFM and EM experiments under certain conditions. These images indicated an outer diameter of 8-12 nm and an inner diameter of the cavity pore of 2.0-2.5 nm 10,14,34 . Nonetheless, the structural transition/conversion between linear-and annular-like structures is still unclear.…”

Section: Introductionmentioning

confidence: 97%

Annular Structures as Intermediates in Fibril Formation of Alzheimer Aβ₁₇₋₄₂

Zheng

Jang

et al. 2008

J. Phys. Chem. B

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We report all-atom molecular dynamics simulations of annular β-amyloid (17-42) structures, singleand double-layered, in solution. We assess the structural stability and association force of Aβ annular oligomers associated through different interfaces, with a mutated sequence (M35A), and with the oxidation state (M35O). Simulation results show that single layered annular models display inherent structural instability: one is broken down into linear-like oligomers, and the other collapses. On the other hand, a double-layered annular structure where the two layers interact through their C-termini to form an NC-CN interface (where N and C are the N and C termini, respectively) exhibits high structural stability over the simulation time due to strong hydrophobic interactions and geometrical constraints induced by the closed circular shape. The observed dimensions and molecular weight of the oligomers from atomic force microscopy (AFM) experiments are found to correspond well to our stable double-layered model with the NC-CN interface. Comparison with K3 annular structures derived from the β 2 -microglobulin suggests that the driving force for amyloid formation is sequence specific, strongly dependent on side-chain packing arrangements, structural morphologies, sequence composition, and residue positions. Combined with our previous simulations of linear-like Aβ, K3 peptide, and sup35-derived GNNQQNY peptide, the annular structures provide useful insight into oligomeric structures and driving forces that are critical in amyloid fibril formation.

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Amyloid pores from pathogenic mutations

Cited by 1,207 publications

References 13 publications

Increased susceptibility to amyloid toxicity in familial Alzheimer's fibroblasts

Increased susceptibility to amyloid toxicity in familial Alzheimer's fibroblasts

Firefly luciferase mutants as sensors of proteome stress

Annular Structures as Intermediates in Fibril Formation of Alzheimer Aβ₁₇₋₄₂

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Amyloid pores from pathogenic mutations

Cited by 1,207 publications

References 13 publications

Increased susceptibility to amyloid toxicity in familial Alzheimer's fibroblasts

Increased susceptibility to amyloid toxicity in familial Alzheimer's fibroblasts

Firefly luciferase mutants as sensors of proteome stress

Annular Structures as Intermediates in Fibril Formation of Alzheimer Aβ17−42

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Annular Structures as Intermediates in Fibril Formation of Alzheimer Aβ₁₇₋₄₂