Genetic modulation of tau phosphorylation in the mouse

Jochen Brich, Feng Shiun Shie, Brian W. Howell, Renhua Li, Katalin Tus, Edward K. Wakeland, Lee-Way Jin, Marc Mumby, Gary Churchill, Joachim Herz, Jonathan A. Cooper

Research output: Contribution to journalArticle

64 Citations (Scopus)

Abstract

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.

Original languageEnglish (US)
Pages (from-to)187-192
Number of pages6
JournalJournal of Neuroscience
Volume23
Issue number1
StatePublished - Jan 1 2003
Externally publishedYes

Fingerprint

Phosphorylation
Alzheimer Disease
Low Density Lipoprotein Receptor-Related Protein-1
Quantitative Trait Loci
Genes
Microtubule Proteins
Dentate Gyrus
Haplotypes
Embryonic Development
Tyrosine
Hippocampus
Animal Models
Neurons
Brain
Proteins

Keywords

  • Alzheimer's disease
  • Disabled-1
  • Genetic interactions
  • Quantitative trait locus analysis
  • Reeler
  • Tau hyperphosphorylation

ASJC Scopus subject areas

  • Neuroscience(all)

Cite this

Brich, J., Shie, F. S., Howell, B. W., Li, R., Tus, K., Wakeland, E. K., ... Cooper, J. A. (2003). Genetic modulation of tau phosphorylation in the mouse. Journal of Neuroscience, 23(1), 187-192.

Genetic modulation of tau phosphorylation in the mouse. / Brich, Jochen; Shie, Feng Shiun; Howell, Brian W.; Li, Renhua; Tus, Katalin; Wakeland, Edward K.; Jin, Lee-Way; Mumby, Marc; Churchill, Gary; Herz, Joachim; Cooper, Jonathan A.

In: Journal of Neuroscience, Vol. 23, No. 1, 01.01.2003, p. 187-192.

Research output: Contribution to journalArticle

Brich, J, Shie, FS, Howell, BW, Li, R, Tus, K, Wakeland, EK, Jin, L-W, Mumby, M, Churchill, G, Herz, J & Cooper, JA 2003, 'Genetic modulation of tau phosphorylation in the mouse', Journal of Neuroscience, vol. 23, no. 1, pp. 187-192.
Brich J, Shie FS, Howell BW, Li R, Tus K, Wakeland EK et al. Genetic modulation of tau phosphorylation in the mouse. Journal of Neuroscience. 2003 Jan 1;23(1):187-192.
Brich, Jochen ; Shie, Feng Shiun ; Howell, Brian W. ; Li, Renhua ; Tus, Katalin ; Wakeland, Edward K. ; Jin, Lee-Way ; Mumby, Marc ; Churchill, Gary ; Herz, Joachim ; Cooper, Jonathan A. / Genetic modulation of tau phosphorylation in the mouse. In: Journal of Neuroscience. 2003 ; Vol. 23, No. 1. pp. 187-192.
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