Potent amyloidogenicity and pathogenicity of Aβ43

The amyloid-beta peptide A beta 42 is known to be a primary amyloidogenic and pathogenic agent in Alzheimer's disease. However, the role of A beta 43, 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 A beta 43. 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 A beta 43, impairment of short-term memory and acceleration of amyloid-b pathology, which accompanied pronounced accumulation of A beta 43 in plaque cores similar in biochemical composition to those observed in the brains of affected individuals. Consistently, A beta 43 showed a higher propensity to aggregate and was more neurotoxic than A beta 42. Other pathogenic presenilin mutations also caused overproduction of A beta 43 in a manner correlating with A beta 42 and with the age of disease onset. These findings indicate that A beta 43, an overlooked species, is potently amyloidogenic, neurotoxic and abundant in vivo.