Presenilin-1 knockin mice reveal loss-of-function mechanism for familial Alzheimer's disease.
Presenilins play essential roles in memory formation, synaptic function, and neuronal survival. Mutations in the Presenilin-1 (PSEN1) gene are the major cause of familial Alzheimer's disease (FAD). How PSEN1 mutations cause FAD is unclear, and pathogenic mechanisms based on gain or loss of function have been proposed. Here, we generated Psen1 knockin (KI) mice carrying the FAD mutation L435F or C410Y. Remarkably, KI mice homozygous for either mutation recapitulate the phenotypes of Psen1(-/-) mice. Neither mutation altered Psen1 mRNA expression, but both abolished γ-secretase activity. Heterozygosity for the KI mutation decreased production of Aβ40 and Aβ42, increased the Aβ42/Aβ40 ratio, and exacerbated Aβ deposition. Furthermore, the L435F mutation impairs hippocampal synaptic plasticity and memory and causes age-dependent neurodegeneration in the aging cerebral cortex. Collectively, our findings reveal that FAD mutations can cause complete loss of Presenilin-1 function in vivo, suggesting that clinical PSEN mutations produce FAD through a loss-of-function mechanism.
Center for Neurologic Diseases, 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 Neurologic Diseases, Department of Neurology, Brigham & Women's Hospital, Harvard Medical School, Boston, MA 02115, USA.
Hirotaka
H
Watanabe
Center for Neurologic Diseases, Department of Neurology, Brigham & Women's Hospital, Harvard Medical School, Boston, MA 02115, USA.
Bei
B
Wu
Center for Neurologic Diseases, Department of Neurology, Brigham & Women's Hospital, Harvard Medical School, Boston, MA 02115, USA.
Sang Hun
SH
Lee
Department of Psychiatry, McLean Hospital, Harvard Medical School, Belmont, MA 02478, USA.
Yan
Y
Li
Department of Psychiatry, McLean Hospital, Harvard Medical School, Belmont, MA 02478, USA.
Evgeny
E
Tsvetkov
Department of Psychiatry, McLean Hospital, Harvard Medical School, Belmont, MA 02478, USA; Program in Neuroscience, Harvard Medical School, Boston, MA 02115, USA.
Vadim Y
VY
Bolshakov
Center for Neurologic Diseases, 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
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
D000544:Alzheimer Disease / Q000235:genetics* / Q000378:metabolism*; D016229:Amyloid beta-Peptides / Q000096:biosynthesis / Q000235:genetics; D000818:Animals; D002540:Cerebral Cortex / Q000378:metabolism / Q000473:pathology; D055879:Gene Knock-In Techniques / Q000379:methods; D006624:Hippocampus / Q000378:metabolism / Q000473:pathology; D006801:Humans; D008297:Male; D008569:Memory Disorders / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D051379:Mice; D057507:Mice, 129 Strain; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009154:Mutation / Q000235:genetics; D055495:Neurogenesis / Q000502:physiology*; D009924:Organ Culture Techniques; D053764:Presenilin-1 / Q000502:physiology*
D016229:Amyloid beta-Peptides; D053764:Presenilin-1; C580804:presenilin 1, mouse