Aggregation State and Neurotoxic Properties of Alzheimer Beta-Amyloid Peptide

Howlett, David; Jennings, Kevin H.; Lee, Dong Hoon; Clark, Michael; Brown, Frank; Wetzel, Ronald; Wood, Stephen; Camilleri, Patrick; Roberts, Gareth W.

doi:10.1006/neur.1995.0003

Cited by 188 publications

(134 citation statements)

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“…We used a CCDM method to examine the possibility that there might be neuronal loss associated with only a subset of plaques. A␤ neurotoxicity has been demonstrated in cell culture (25)(26)(27)(28)(29)(30)(31) where the extent of toxicity is clearly influenced by the aggregation state of A␤, with fibrillar A␤ being far more toxic. We show evidence for a specific association between ThioS A␤ plaques and neuronal loss in both human brain and a transgenic model of AD.…”

Section: Discussionmentioning

confidence: 99%

Neurotoxic effects of thioflavin S-positive amyloid deposits in transgenic mice and Alzheimer's disease

Urbanc

Cruz

et al. 2002

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

212

146

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Despite extensive deposition of putatively neurotoxic amyloid-␤ (A␤) protein in the brain, it has not been possible to demonstrate an association of A␤ deposits with neuronal loss in Alzheimer's disease (AD), and neuronal loss is minimal in transgenic mouse models of AD. Using triple immunostaining confocal microscopy and analyzing the images with the cross-correlation density map method from statistical physics, we directly compared A␤ deposition, A␤ morphology, and neuronal architecture. We found dramatic, focal neuronal toxicity associated primarily with thioflavin S-positive fibrillar A␤ deposits in both AD and PSAPP mice. These results, along with computer simulations, suggest that A␤ develops neurotoxic properties in vivo when it adopts a fibrillar ␤-pleated sheet conformation.T he primary pathologic features of Alzheimer's disease (AD) are amyloid deposition, neurofibrillary tangle formation, and neuronal loss. There is substantial indirect evidence implicating amyloid-␤ (A␤) protein in the pathological cascade leading to neuronal loss in AD (1). Presenilin-1 (PS1), presenilin-2, and amyloid precursor protein (APP) mutations causing familial AD and the apolipoprotein E 4 allele risk factor for AD all increase plasma, fibroblast, or brain levels of A␤ or A␤x-42͞43 in AD and transgenic mice (2-10). However, paradoxically, in human AD, the total amount of extracellular A␤ has little or no correlation with the amount of neuronal loss, which exceeds 50% in vulnerable regions of the cortex (11-13). Although quantitative stereological studies of neuron number in CA1 of APP23 (APPSw overexpressing) mice show a small decrement in neuronal number, no neuronal loss was detected in APP23 mice in the cortex (despite high levels of amyloid deposits) or in the hippocampus or cortex of PDAPP (APP V717F ), Tg2576 (APP KM670Ϫ1NL ), and PSAPP (APPSw ϫ PS1 M146L ) mice (14-17), arguing that, in contrast to in vitro data, A␤ deposits are not neurotoxic in vivo.A␤ deposits have a variety of morphologies, reflecting different amounts of fibrillar, ␤-pleated sheet conformation, ranging from ''diffuse'' deposits with little ␤-pleated sheet to dense core compact deposits that can be stained with dyes such as thioflavin S (ThioS) or Congo red; the extent of associated gliosis and synaptic loss is associated with the morphology of the A␤ deposits. We now test the hypothesis that only a subset of A␤ deposits is biologically toxic. In our approach we adopt a statistical physics method, i.e., the density map method, which is typically used in condensed matter physics to study local molecular organization, and which we have recently applied successfully to study the microcolumnar structure in brains of AD patients and patients with Lewy body dementia (18). We generalize the density map method to study the relationship between two different populations and then apply this method, which we call the cross-correlation density map (CCDM) method, to study the local neuronal organization surrounding A␤-immunoreactive deposits. We find evidence...

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Section: Discussionmentioning

confidence: 99%

Neurotoxic effects of thioflavin S-positive amyloid deposits in transgenic mice and Alzheimer's disease

Urbanc

Cruz

et al. 2002

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

212

146

View full text Add to dashboard Cite

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“…In previous cell culture studies, the most important predictor of A␤ toxicity was the macromolecular state of the A␤ peptides with only aged or aggregated A␤ peptides (including fibrils, protofibrils, and/or low molecular weight intermediates) consistently eliciting toxic responses (12)(13)(14)(15)(16)(17)(18). Additionally, both the L-and D-enantiomers of A␤ exhibited nearly identical structural characteristics and induced similar levels of toxicity, implying that A␤ neurotoxicity was mediated by A␤ fibril features instead of any stereoisomer-specific interactions (79).…”

Section: Discussionmentioning

confidence: 99%

“…The toxicity of A␤ has been directly linked to structure and amyloid content. In an aggregated state (containing fibrils, protofibrils, and low molecular weight intermediates), A␤ has been consistently shown to be toxic to neurons in culture (12)(13)(14)(15)(16)(17)(18). Although there is some disagreement as to the exact structure of the aggregated species associated with toxicity, whether it be a protofibril (14,19), a diffusible, nonfibrillar ligand (20), or some other low molecular weight intermediate (19), toxicity is associated with peptide structures that are part of the aggregation pathway associated with amyloid formation.…”

mentioning

confidence: 99%

The Role of G Protein Activation in the Toxicity of Amyloidogenic Aβ-(1–40), Aβ-(25–35), and Bovine Calcitonin

Rymer

Good

2001

Journal of Biological Chemistry

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More than 16 different proteins have been identified as amyloid in clinical diseases; among these, ␤-amyloid (A␤) of Alzheimer's disease is the best characterized. In the present study, we performed experiments with A␤ and calcitonin, another amyloid-forming peptide, to examine the role of G protein activation in amyloid toxicity. We demonstrated that the peptides, when prepared under conditions that promoted ␤-sheet and amyloid fibril (or protofibril) formation, increased high affinity GTPase activity, but the nonamyloidogenic peptides had no discernible effects on GTP hydrolysis. These increases in GTPase activity were correlated to toxicity. In addition, G protein inhibitors significantly reduced the toxic effects of the amyloidogenic A␤ and calcitonin peptides. Our results further indicated that the amyloidogenic peptides significantly increased GTPase activity of purified G␣ o and G␣ i subunits and that the effect was not receptor-mediated. Collectively, these results imply that the amyloidogenic structure, regardless of the actual peptide or protein sequence, may be sufficient to cause toxicity and that toxicity is mediated, at least partially, through G protein activation. Our abilities to manipulate G protein activity may lead to novel treatments for Alzheimer's disease and the other amyloidoses.

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“…Amyloid-␤ neurotoxicity has been shown to correlate with the presence of fibrils or ␤-sheet structures (Simmons et al, 1994;Howlett et al, 1995;Seilheimer et al, 1997). However, the mechanisms by which A␤ aggregation mediates neuronal cell death are unknown.…”

Section: Introductionmentioning

confidence: 99%

Nucleation-Dependent Polymerization Is an Essential Component of Amyloid-Mediated Neuronal Cell Death

Wogulis¹,

Wright²,

Cunningham³

et al. 2005

J. Neurosci.

211

165

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Accumulating evidence suggests that amyloid protein aggregation is pathogenic in many diseases, including Alzheimer's disease. However, the mechanisms by which protein aggregation mediates cellular dysfunction and overt cell death are unknown. Recent reports have focused on the potential role of amyloid oligomers or protofibrils as a neurotoxic form of amyloid-␤ (A␤) and related amyloid aggregates. Here we describe studies indicating that overt neuronal cell death mediated by A␤ 1-40 is critically dependent on ongoing A␤ 1-40 polymerization and is not mediated by a single stable species of neurotoxic aggregate. The extent and rate of neuronal cell death can be controlled by conditions that alter the rate of A␤ polymerization. The results presented here indicate that protofibrils and oligomeric forms of A␤ most likely generate neuronal cell death through a nucleation-dependent process rather than acting as direct neurotoxic ligands. These findings bring into question the use of the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide formazan assay (MTT assay) as a reporter of A␤-mediated neuronal cell death and suggest that diffusible A␤ protofibrils and oligomers more likely mediate subtle alterations of synaptic function and long-term potentiation rather than overt neuronal cell death. These results have been extended to A␤ 1-42 , the non-A␤ component of Alzheimer's disease amyloid plaques, and human amylin, suggesting that nucleationdependent polymerization is a common mechanism of amyloid-mediated neuronal cell death. Our findings indicate that ongoing amyloid fibrillogenesis may be an essential mechanistic process underlying the pathogenesis associated with protein aggregation in amyloid disorders.

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Aggregation State and Neurotoxic Properties of Alzheimer Beta-Amyloid Peptide

Cited by 188 publications

References 0 publications

Neurotoxic effects of thioflavin S-positive amyloid deposits in transgenic mice and Alzheimer's disease

Neurotoxic effects of thioflavin S-positive amyloid deposits in transgenic mice and Alzheimer's disease

The Role of G Protein Activation in the Toxicity of Amyloidogenic Aβ-(1–40), Aβ-(25–35), and Bovine Calcitonin

Nucleation-Dependent Polymerization Is an Essential Component of Amyloid-Mediated Neuronal Cell Death

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