14 Jan 2003

Deficiencies in a component of the reelin developmental signaling cascade produces a mouse that mimics the increased phosphorylation of tau protein seen in Alzheimer's and other neurodegenerative tauopathies, according to a report in the current issue of the Journal of Neuroscience.

The "Tauists" have been less fortunate than the "Baptists" when it comes to animal models, but that has begun to change. In the past few years, there have been a number of reports of transgenic or mutant mouse models suitable for studying hyperphosphorylation and accumulation of tau protein (see ARF related news; ARF related news). These include the "reeler" strain of mice, in whom absence or mutation of the reelin gene interferes with cortical development to create ataxic mice that die young. This phenotype also appears when one interferes experimentally with proteins that interact with reelin, including two reelin receptors, ApoER2 and VLDLR, and the product of the gene Disabled1, or Dab1.

Jonathan Cooper and associates at the University of Texas Southwestern Medical Center in Dallas, Texas, have shown previously that interference with reelin or its two receptors causes tau hyperphosphorylation (Heisberger et al., 1999). In the current paper, they report the same for mice with either mutated or deleted Dab1 genes. This hyperphosphorylation appeared only in neurons of the hippocampus proper and the dentate gyrus, along with fiber tracts of the corpus callosum and the fasciculus retroflexus.

The genetic background played heavily into this. The same genetic manipulations caused tau hyperphosphorylation in Dab1 knockout and mutant mice on a background of the 129Sv x C57BL/6 (or SB) hybrid strain that is popular for generating knockout mice but not in the BALB/cByJ (or CC) strain. The survival effect also correlates with this difference: the SB Dab1-deficient mice die much earlier than the CC Dab1-deficient mice.

Quantitative trait locus analysis of the Dab1 knockout mice revealed one significant and three suggestive chromosomal loci that modulate tau phosphorylation. The significant locus on chromosome 16 is near the gene for APP, and one of the suggestive loci lies near the gene encoding PS-1 on chromosome 12. These proximities lead the authors to suggest the possibility that "polymorphisms in genes that cause neurodegeneration and tau hyperphosphorylation in humans also regulate tau hyperphosphorylation when reelin-Dab1 signaling is defective." Brich et al. stress that definitive proof of whether reelin and its associated proteins are active in regulating tau phosphorylation beyond the developmental period awaits the introduction of conditional knockout models-mice in which the activity of reelin, Dab1, and the receptors can be permitted long enough to allow normal development to take place before the gene activity is knocked out.—Hakon Heimer