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 Aβ40 and Aβ42 are undetectable in KI/KI brains and reduced in KI/+ brains, though the Aβ42/Aβ40 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 Aβ43. Similar to Aβ40 and Aβ42, production of Aβ43 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 γ-secretase activity, including impaired Aβ production in the brain. This Matters Arising Response paper addresses the Veugelen et al. (2016) Matters Arising paper, published concurrently in Neuron.
Department of Neurology, Brigham & Women's Hospital, Harvard Medical School, Boston, MA 02115, USA; Center for Human Genetic Research, Department of Neurology, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA.
Dan
D
Xia
Center for Human Genetic Research, Department of Neurology, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA; Program in Neuroscience, Harvard Medical School, Boston, MA 02115, USA. Electronic address: kelleher@helix.mgh.harvard.edu.
Raymond J
RJ
Kelleher
Department of Neurology, Brigham & Women's Hospital, Harvard Medical School, Boston, MA 02115, USA; Program in Neuroscience, Harvard Medical School, Boston, MA 02115, USA. Electronic address: jshen@rics.bwh.harvard.edu.
Jie
J
Shen
D053829:Amyloid Precursor Protein Secretases / Q000378:metabolism; D016229:Amyloid beta-Peptides / Q000096:biosynthesis / Q000378:metabolism*; D000818:Animals; D001921:Brain / Q000378:metabolism; D055879:Gene Knock-In Techniques; D006720:Homozygote; D051379:Mice; D009154:Mutation; D010446:Peptide Fragments / Q000096:biosynthesis / Q000378:metabolism*; D053764:Presenilin-1 / Q000235:genetics*
D016229:Amyloid beta-Peptides; D010446:Peptide Fragments; D053764:Presenilin-1; C098994:amyloid beta-protein (1-43); C580804:presenilin 1, mouse; D053829:Amyloid Precursor Protein Secretases