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Title
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Potent amyloidogenicity and pathogenicity of
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Author
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Abstract
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| The amyloid-β peptide Aβ42 is known to be a primary amyloidogenic and pathogenic agent in Alzheimer's disease. However, the role of Aβ43, which is found just as frequently in the brains of affected individuals, remains unresolved. We generated knock-in mice containing a pathogenic presenilin-1 R278I mutation that causes overproduction of Aβ43. Homozygosity was embryonic lethal, indicating that the mutation involves a loss of function. Crossing amyloid precursor protein transgenic mice with heterozygous mutant mice resulted in elevated Aβ43, impairment of short-term memory and acceleration of amyloid-β pathology, which accompanied pronounced accumulation of Aβ43 in plaque cores similar in biochemical composition to those observed in the brains of affected individuals. Consistently, Aβ43 showed a higher propensity to aggregate and was more neurotoxic than Aβ42. Other pathogenic presenilin mutations also caused overproduction of Aβ43 in a manner correlating with Aβ42 and with the age of disease onset. These findings indicate that Aβ43, an overlooked species, is potently amyloidogenic, neurotoxic and abundant in vivo. |
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Language
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English
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Source (journal)
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Nature neuroscience. - London
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Publication
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London
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2011
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ISSN
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1097-6256
[Print]
1546-1726
[Online]
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DOI
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10.1038/NN.2858
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Volume/pages
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14
:8
(2011)
, p. 1023-1032
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ISI
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000293123700016
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Full text (Publisher's DOI)
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