title: Potent amyloidogenicity and pathogenicity of Aβ43.
abstract: 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.
authors: Laboratory for Proteolytic Neuroscience, RIKEN Brain Science Institute, Wako-shi, Saitama, Japan.
authors: Takashi
authors: T
authors: Saito
authors: Takahiro
authors: T
authors: Suemoto
authors: Nathalie
authors: N
authors: Brouwers
authors: Kristel
authors: K
authors: Sleegers
authors: Satoru
authors: S
authors: Funamoto
authors: Naomi
authors: N
authors: Mihira
authors: Yukio
authors: Y
authors: Matsuba
authors: Kazuyuki
authors: K
authors: Yamada
authors: Per
authors: P
authors: Nilsson
authors: Jiro
authors: J
authors: Takano
authors: Masaki
authors: M
authors: Nishimura
authors: Nobuhisa
authors: N
authors: Iwata
authors: Christine
authors: C
authors: Van Broeckhoven
authors: Yasuo
authors: Y
authors: Ihara
authors: Takaomi C
authors: TC
authors: Saido
mesh_terms: D000328:Adult; D000367:Age Factors; D000368:Aged; D000369:Aged, 80 and over; D000544:Alzheimer Disease / Q000150:complications / Q000235:genetics* / Q000378:metabolism* / Q000473:pathology*; D016229:Amyloid beta-Peptides / Q000378:metabolism*; D016564:Amyloid beta-Protein Precursor / Q000235:genetics; D000818:Animals; D001120:Arginine / Q000235:genetics; D045744:Cell Line, Tumor; D002540:Cerebral Cortex / Q000473:pathology; D003072:Cognition Disorders / Q000209:etiology*; D004195:Disease Models, Animal; D004622:Embryo, Mammalian; D004797:Enzyme-Linked Immunosorbent Assay / Q000379:methods; D005260:Female; D005786:Gene Expression Regulation / Q000235:genetics; D006801:Humans; D047468:Immunoprecipitation / Q000379:methods; D007532:Isoleucine / Q000235:genetics; D007770:L-Lactate Dehydrogenase / Q000378:metabolism; D008297:Male; D018782:Maze Learning / Q000502:physiology; D008570:Memory, Short-Term / Q000502:physiology; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D008875:Middle Aged; D009154:Mutation / Q000235:genetics; D009447:Neuroblastoma; D009474:Neurons / Q000378:metabolism; D010446:Peptide Fragments / Q000378:metabolism*; D053764:Presenilin-1 / Q000235:genetics
chemical_list: D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; C508853:PSEN1 protein, human; D010446:Peptide Fragments; D053764:Presenilin-1; C098994:amyloid beta-protein (1-43); D007532:Isoleucine; D001120:Arginine; D007770:L-Lactate Dehydrogenase