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 RIS Download
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