Abstract
We have developed a presenilin-1 (PS1) conditional knockout mouse (cKO), in which PS1 inactivation is restricted to the postnatal forebrain. The PS1 cKO mouse is viable and exhibits no gross abnormalities. The carboxy-terminal fragments of the amyloid precursor protein differentially accumulate in the cerebral cortex of cKO mice, while generation of beta-amyloid peptides is reduced. Expression of Notch downstream effector genes, Hes1, Hes5, and Dll1, is unaffected in the cKO cortex. Although basal synaptic transmission, long-term potentiation, and long-term depression at hippocampal area CA1 synapses are normal, the PS1 cKO mice exhibit subtle but significant deficits in long-term spatial memory. These results demonstrate that inactivation of PS1 function in the adult cerebral cortex leads to reduced Abeta generation and subtle cognitive deficits without affecting expression of Notch downstream genes.
Publication types
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Alzheimer Disease / genetics*
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Alzheimer Disease / metabolism
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Alzheimer Disease / physiopathology
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Amyloid beta-Peptides / biosynthesis*
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Amyloid beta-Peptides / genetics
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Amyloid beta-Protein Precursor / genetics
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Amyloid beta-Protein Precursor / metabolism*
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Animals
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Axons / metabolism
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Axons / ultrastructure
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Cerebral Cortex / growth & development
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Cerebral Cortex / metabolism
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Cerebral Cortex / physiopathology
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Disease Models, Animal
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Gene Expression Regulation, Developmental / physiology
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Genetic Vectors / physiology
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Hippocampus / growth & development
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Hippocampus / metabolism
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Hippocampus / physiopathology
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Maze Learning / physiology
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Membrane Proteins / deficiency*
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Membrane Proteins / genetics
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Membrane Proteins / metabolism
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Memory Disorders / genetics
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Memory Disorders / metabolism
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Memory Disorders / physiopathology
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Mice
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Mice, Knockout / genetics
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Mice, Knockout / growth & development*
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Mice, Knockout / metabolism
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Neural Pathways / growth & development
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Neural Pathways / metabolism
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Neural Pathways / physiopathology
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Neuronal Plasticity / genetics*
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Presenilin-1
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Receptors, Notch
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Signal Transduction / genetics
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Space Perception / physiology
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Synaptic Transmission / genetics*
Substances
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Amyloid beta-Peptides
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Amyloid beta-Protein Precursor
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Membrane Proteins
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Presenilin-1
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Receptors, Notch