Loss of Aβ43 Production Caused by Presenilin-1 Mutations in the Knockin Mouse Brain

We recently reported that homozygous Presenilin-1 (Psen1) knockin (KI) mice carrying the familial Alzheimer's disease (FAD) mutation L435F or C410Y recapitulate the phenotypes of Psen1(-/-) mice. Production and steady-state levels of A beta 40 and A beta 42 are undetectable in KI/KI brains and reduced in KI/+ brains, though the A beta 42/A beta 40 ratio is slightly increased in KI/+ brains. Moreover, the FAD mutation impairs synaptic function, learning and memory, and age-dependent neuronal survival in the adult brain. Here we extend our analysis of the effects of the L435F and C410Y mutations to the generation of A beta 43. Similar to A beta 40 and A beta 42, production of A beta 43 is undetectable in KI/KI brains and reduced in KI/+ brains. These results support our previous conclusions that the L435F and C410Y mutations cause loss of Presenilin function and gamma-secretase activity, including impaired A beta production in the brain. This Matters Arising Response paper addresses the Veugelen et al. (2016) Matters Arising paper, published concurrently in Neuron.