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Potent amyloidogenicity and pathogenicity of Aβ43.

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.

Pubmed ID: 21725313

Authors

  • Saito T
  • Suemoto T
  • Brouwers N
  • Sleegers K
  • Funamoto S
  • Mihira N
  • Matsuba Y
  • Yamada K
  • Nilsson P
  • Takano J
  • Nishimura M
  • Iwata N
  • Van Broeckhoven C
  • Ihara Y
  • Saido TC

Journal

Nature neuroscience

Publication Data

August 27, 2011

Associated Grants

None

Mesh Terms

  • Adult
  • Age Factors
  • Aged
  • Aged, 80 and over
  • Alzheimer Disease
  • Amyloid beta-Peptides
  • Amyloid beta-Protein Precursor
  • Animals
  • Arginine
  • Cell Line, Tumor
  • Cerebral Cortex
  • Cognition Disorders
  • Disease Models, Animal
  • Embryo, Mammalian
  • Enzyme-Linked Immunosorbent Assay
  • Female
  • Gene Expression Regulation
  • Humans
  • Immunoprecipitation
  • Isoleucine
  • L-Lactate Dehydrogenase
  • Male
  • Maze Learning
  • Memory, Short-Term
  • Mice
  • Mice, Inbred C57BL
  • Mice, Transgenic
  • Middle Aged
  • Mutation
  • Neuroblastoma
  • Neurons
  • Peptide Fragments
  • Presenilin-1