Mice with Combined Gene Knock-Outs Reveal Essential and Partially Redundant Functions of Amyloid Precursor Protein Family Members
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Open Access
- 1 November 2000
- journal article
- Published by Society for Neuroscience in Journal of Neuroscience
- Vol. 20 (21) , 7951-7963
- https://doi.org/10.1523/jneurosci.20-21-07951.2000
Abstract
The amyloid precursor protein (APP) involved in Alzheimer's disease is a member of a larger gene family including amyloid precursor-like proteins APLP1 and APLP2. We generated and examined the phenotypes of mice lacking individual or all possible combinations of APP family members to assess potential functional redundancies within the gene family. Mice deficient for the nervous system-specific APLP1 protein showed a postnatal growth deficit as the only obvious abnormality. In contrast to this minor phenotype, APLP2−/−/APLP1−/−and APLP2−/−/APP−/−mice proved lethal early postnatally. Surprisingly, APLP1−/−/APP−/−mice were viable, apparently normal, and showed no compensatory upregulation of APLP2 expression. These data indicate redundancy between APLP2 and both other family members and corroborate a key physiological role for APLP2. This view gains further support by the observation that APLP1−/−/APP−/−/APLP2+/−mice display postnatal lethality. In addition, they provide genetic evidence for at least some distinct physiological roles of APP and APLP2 by demonstrating that combinations of single knock-outs with the APLP1 mutation resulted in double mutants of clearly different phenotypes, being either lethal, or viable. None of the lethal double mutants displayed, however, obvious histopathological abnormalities in the brain or any other organ examined. Moreover, cortical neurons from single or combined mutant mice showed unaltered survival rates under basal culture conditions and unaltered susceptibility to glutamate excitotoxicityin vitro.Keywords
This publication has 50 references indexed in Scilit:
- Involvement of Activated Caspase‐3‐Like Proteases in N‐Methyl‐D‐Aspartate‐Induced Apoptosis in Cerebrocortical NeuronsJournal of Neurochemistry, 2000
- Hypersensitivity to seizures in β-amyloid precursor protein deficient miceCell Death & Differentiation, 1998
- Neurobehavioral development, adult openfield exploration and swimming navigation learning in mice with a modified β-amyloid precursor protein geneBehavioural Brain Research, 1998
- Alzheimer Amyloid Protein Precursor Is Localized in Nerve Terminal Preparations to Rab5-containing Vesicular Organelles Distinct from Those Implicated in the Synaptic Vesicle PathwayJournal of Biological Chemistry, 1996
- Novel Regulation of Chondroitin Sulfate Glycosaminoglycan Modification of Amyloid Precursor Protein and Its Homologue, APLP2Published by Elsevier ,1995
- Intracellular routing of human amyloid protein precursor: Axonal delivery followed by transport to the dendritesJournal of Neuroscience Research, 1995
- β-amyloid precursor protein-deficient mice show reactive gliosis and decreased locomotor activityCell, 1995
- Trafficking of cell surface beta-amyloid precursor protein: retrograde and transcytotic transport in cultured neurons.The Journal of cell biology, 1995
- Secreted forms of β‐amyloid precursor protein modulate dendrite outgrowth and calcium responses to glutamate in cultured embryonic hippocampal neuronsJournal of Neurobiology, 1994
- Isolation and characterization of APLP2 encoding a homologue of the Alzheimer's associated amyloid β protein precursorNature Genetics, 1993