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The Journal of Neuroscience, January 1, 2003, 23(1):187-192

Genetic Modulation of Tau Phosphorylation in the Mouse

Jochen Brich¹, Feng-Shiun Shie⁴, Brian W. Howell⁵, Renhua Li⁶, Katalin Tus², Edward K. Wakeland², Lee-Way Jin⁴, Marc Mumby³, Gary Churchill⁶, Joachim Herz¹, and Jonathan A. Cooper⁵

Departments of ¹ Molecular Genetics, ² Immunology, and ³ Pharmacology, University of Texas Southwestern Medical Center, Dallas, Texas 75390, ⁴ Alzheimer Disease Research Center, University of Washington, Seattle, Washington 98195, ⁵ Fred Hutchinson Cancer Research Center, Seattle, Washington 98109, and ⁶ The Jackson Laboratory, Bar Harbor, Maine 04609

The axonal microtubule stabilizing protein tau is hyperphosphorylated in several neurodegenerative conditions, including Alzheimer's disease, yet the genes that regulate tau phosphorylation are largely unknown. Disabled-1 (Dab1) is a cytoplasmic adapter protein that interacts with apolipoprotein E (ApoE) receptors and controls neuronal positioning during embryonic brain development. We have investigated the role of Dab1 in tau phosphorylation. We found that wild-type Dab1, but not a mutant lacking tyrosine phosphorylation sites, protects mice from the hyperphosphorylation of tau. However, the absence of Dab1 is not sufficient to cause tau hyperphosphorylation, because hyperphosphorylation is manifested only when Dab1 is mutated in specific mouse strain backgrounds. Tau hyperphosphorylation correlates with early death in susceptible mouse strains, and it occurs in the neurons of the hippocampus and dentate gyrus. By quantitative trait locus (QTL) analysis of Dab1-deficient mice on a hybrid strain background, we uncovered one significant and three suggestive chromosomal loci that modulate tau phosphorylation. Two of these QTL regions contain genes that are defective in early onset Alzheimer's disease. Our findings suggest that Dab1 gene disruption sensitizes mice to tau hyperphosphorylation contingent on specific haplotypes that are linked to Alzheimer's disease loci. Dab1 mutant mice provide an animal model for studying the relationships between ApoE receptors, tau hyperphosphorylation, and Alzheimer's disease.

Key words: Reeler; Disabled-1; tau hyperphosphorylation; quantitative trait locus analysis; Alzheimer's disease; genetic interactions

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Copyright © 2003 Society for Neuroscience  0270-6474/03/231187-06$05.00/0

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