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The Journal of Neuroscience, November 1, 2000, 20(21):7951-7963

Mice with Combined Gene Knock-Outs Reveal Essential and Partially Redundant Functions of Amyloid Precursor Protein Family Members

Sabine Heber¹, Jochen Herms², Vladan Gajic⁷, Johannes Hainfellner³, Adriano Aguzzi³, Thomas Rülicke⁴, Hans Kretzschmar², Cornelia von Koch⁵, Sangram Sisodia⁵, Phillippe Tremml⁶, Hans-Peter Lipp⁶, David P. Wolfer⁶, and Ulrike Müller^{1, 7}

¹ Department of Neurochemistry, Max-Planck-Institute for Brain Research, D-60528 Frankfurt, Germany, ² Department of Neuropathology, University of Göttingen, Göttingen, Germany, ³ Institute of Neuropathology, and ⁴ Biologisches Zentrallabor, University Hospital, 8091 Zürich, ⁵ Department of Neurobiology, Pharmacology and Physiology, University of Chicago, Chicago, Illinois 60637, and Institutes for ⁶ Anatomy, and ⁷ Molecular Biology, University of Zürich, 8057 Zürich, Switzerland

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 excitotoxicity in vitro.

Key words: amyloid precursor protein; amyloid precursor-like protein; knock-out mice; functional redundancy; excitotoxicity; cortical neurons; Alzheimer's disease

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Copyright © 2000 Society for Neuroscience  0270-6474/00/20217951-13$05.00/0

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