The DOI matches its Crossref record; 37 of the 37 references it cites were found in a registry or an index.
A new amyloid β variant favoring oligomerization in Alzheimer's‐type dementia
Abstract
Objective: Soluble oligomers of amyloid β (Aβ), rather than amyloid fibrils, have been proposed to initiate synaptic and cognitive dysfunction in Alzheimer's disease (AD). However, there is no direct evidence in humans that this mechanism can cause AD. Here, we report a novel amyloid precursor protein ( APP ) mutation that may provide evidence to address this question. Methods: A Japanese pedigree showing Alzheimer's‐type dementia was examined for mutations in APP, PSEN1, and PSEN2. In addition, 5,310 Japanese people, including 2,121 patients with AD, were screened for the novel APP mutation. The pathogenic effects of this mutation on Aβ production, degradation, aggregation, and synaptotoxicity were also investigated. Results: We identified a novel APP mutation (E693Δ) producing variant Aβ lacking gulutamate‐22 (E22Δ) in Japanese pedigrees showing Alzheimer's‐type dementia and AD. Although the secretion of total Aβ was markedly reduced by this mutation, the variant Aβ was more resistant to proteolytic degradation. The mutant peptides showed the unique aggregation property of enhanced oligomerization but no fibrillization, and inhibited hippocampal long‐term potentiation more potently than wild‐type peptide in rats in vivo. Consistent with the nonfibrillogenic property of the variant Aβ, a very low amyloid signal was observed in the patient's brain on positron emission tomography using Pittsburgh compound‐B. Interpretation: The E693Δ mutation has been suggested as a cause of dementia because of enhanced formation of synaptotoxic Aβ oligomers. Our findings may provide genetic validation in humans for the emerging hypothesis that the synaptic and cognitive impairment in AD is primarily caused by soluble Aβ oligomers. Ann Neurol 2008
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1 retracted
RETRACTED ARTICLE: A specific amyloid-β protein assembly in the brain impairs memory
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Alzheimer's Disease Is a Synaptic Failure
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Cited by
Protein Misfolding, Amyloid Formation, and Human Disease: A Summary of Progress Over the Last Decade
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The toxic Aβ oligomer and Alzheimer's disease: an emperor in need of clothes
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The Amyloid-β Pathway in Alzheimer’s Disease
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Alzheimer Mechanisms and Therapeutic Strategies
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Defeating Alzheimer's disease and other dementias: a priority for European science and society
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Metadata
- Authors
- Tomiyama, T., Nagata, T., Shimada, H., Teraoka, R., Fukushima, A., Kanemitsu, H., Takuma, H., Kuwano, R., Imagawa, M., Ataka, S., Wada, Y., Yoshioka, E., Nishizaki, T., Watanabe, Y., & Mori, H.
- Venue
- Annals of Neurology
- Publisher
- Wiley
- Published
- 2008-03
- Volume
- 63
- Issue
- 3
- Pages
- 377-387
- ISSN
- 0364-5134 (ISSN-L)
- 1531-8249
- OpenAlex
- W1969099023
- Cited by
- 421
- References
- 37
- FWCI
- 14.28
- Type
- journal article
- Language
- en
- Open access
- closed
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- Tomiyama, T., Nagata, T., Shimada, H., Teraoka, R., Fukushima, A., Kanemitsu, H., Takuma, H., Kuwano, R., Imagawa, M., Ataka, S., Wada, Y., Yoshioka, E., Nishizaki, T., Watanabe, Y., & Mori, H. (2008). A new amyloid β variant favoring oligomerization in Alzheimer's‐type dementia. Annals of Neurology. https://doi.org/10.1002/ana.21321
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Contains information from the Semantic Scholar Academic Graph Datasets, made available under the ODC Attribution License (ODC-BY 1.0).
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