Alzheimer's Aβ42 and Aβ40 peptides form interlaced amyloid fibrils

Gu, Lin; Guo, Zhefeng

doi:10.1111/jnc.12202

Cited by 222 publications

(166 citation statements)

References 31 publications

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“…The increased activation of kinases results in dendritic spine loss, tau hyperphospho-rylation, cytoskeletal compromise, and accumulation of NFTs. A number of factors are released by damaged neurons and induce the generation of free radicals and inflammation, whose effects are intensified by proinflammatory cytokine release (224).…”

Section: Cerebral Toxocariasis Versus Alzheimer's Disease: a Silent Pmentioning

confidence: 99%

Cerebral Toxocariasis: Silent Progression to Neurodegenerative Disorders?

et al. 2015

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SUMMARY Toxocara canis and T. cati are highly prevalent nematode infections of the intestines of dogs and cats. In paratenic hosts, larvae do not mature in the intestine but instead migrate through the somatic tissues and organs of the body. The presence of these migrating larvae can contribute to pathology. Toxocara larvae can invade the brains of humans, and while case descriptions of cerebral toxocariasis are historically rare, improved diagnosis and greater awareness have contributed to increased detection. Despite this, cerebral or neurological toxocariasis (NT) remains a poorly understood phenomenon. Furthermore, our understanding of cognitive deficits due to toxocariasis in human populations remains particularly deficient. Recent data describe an enhanced expression of biomarkers associated with brain injury, such as GFAP, AβPP, transforming growth factor β1 (TGF-β1), NF-L, S100B, tTG, and p-tau, in mice receiving even low doses of Toxocara ova. Finally, this review outlines a hypothesis to explore the relationship between the presence of T. canis larvae in the brain and the progression of Alzheimer's disease (AD) due to enhanced AD-associated neurodegenerative biomarker expression.

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Section: Cerebral Toxocariasis Versus Alzheimer's Disease: a Silent Pmentioning

confidence: 99%

Cerebral Toxocariasis: Silent Progression to Neurodegenerative Disorders?

et al. 2015

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“…Full-length Aβ was cleaved from the fusion protein with Usp2cc using a previously described protocol (Gu and Guo, 2013; Gu et al, 2013). …”

Section: Methodsmentioning

confidence: 99%

A new structural model of Alzheimer’s Aβ42 fibrils based on electron paramagnetic resonance data and Rosetta modeling

Tran

Jiang

et al. 2016

Journal of Structural Biology

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Brain deposition of Aβ in the form of amyloid plaques is a pathological hallmark of Alzheimer's disease. There are two major species of Aβ in the brain: Aβ42 and Aβ40. Although Aβ40 is several-fold more abundant than Aβ42 in soluble form, Aβ42 is the major component of amyloid plaques. Structural knowledge of Aβ42 fibrils is important both for understanding the process of Aβ aggregation and for designing fibril-targeting drugs. Here we report site-specific structural information of Aβ42 fibrils at 22 residue positions based on electron paramagnetic resonance data. In combination with structure prediction program Rosetta, we modeled Aβ42 fibril structure at atomic resolution. Our Aβ42 fibril model consists of four parallel in-register β-sheets: βN (residues ~7-13), β1 (residues ~17-20), β2 (residues ~32-36), and βC (residues 39-41). The region of β1-loop-β2 in Aβ42 fibrils adopts similar structure as that in Aβ40 fibrils. This is consistent with our cross seeding data that Aβ42 fibril seeds shortened the lag phase of Aβ40 fibrillization. On the other hand, Aβ42 fibrils contain a C-terminal β-arc-β motif with a special turn, termed “arc”, at residues 37-38, which is absent in Aβ40 fibrils. Our results can explain both the higher aggregation propensity of Aβ42 and the importance of Aβ42 to Aβ40 ratio in the pathogenesis of Alzheimer's disease.

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“…The EPR sample can be in solutions, aggregates, or membrane environments, and of any size. As shown previously in the studies of A␤ and yeast prion protein Ure2p, EPR can resolve structural heterogeneity and separate different structural states (23)(24)(25)(26). Distance measurements with continuous-wave and pulsed EPR can cover a wide range of distances from 5 to 70 Å (27,28).…”

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confidence: 98%

Antiparallel Triple-strand Architecture for Prefibrillar Aβ42 Oligomers

Liu

Stroud

et al. 2014

Journal of Biological Chemistry

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Background: Soluble A␤42 oligomers, rather than insoluble amyloid fibrils, are toxic species in Alzheimer's disease. Results: We obtained structural restraints at all 42 residue positions in A␤42 oligomers and performed structural modeling. Conclusion: In oligomers, each A␤42 protein forms a single ␤-sheet with three antiparallel ␤-strands. Significance: Our novel structural model provides new structural framework for understanding oligomer-fibril interconversion and designing oligomer-targeted therapeutics.

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Alzheimer's Aβ42 and Aβ40 peptides form interlaced amyloid fibrils

Cited by 222 publications

References 31 publications

Cerebral Toxocariasis: Silent Progression to Neurodegenerative Disorders?

Cerebral Toxocariasis: Silent Progression to Neurodegenerative Disorders?

A new structural model of Alzheimer’s Aβ42 fibrils based on electron paramagnetic resonance data and Rosetta modeling

Antiparallel Triple-strand Architecture for Prefibrillar Aβ42 Oligomers

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