Zhang et al. have published a very interesting study showing that deletion of the striatal-enriched tyrosine phosphatase (STEP) gene protects the 3xTg animal model of Alzheimer disease. The interesting part of this study is that the protection is not at the level of reducing Aβ or phospho-tau, but at the level of protecting neurons from synaptotoxic effects of AD pathological changes. The 3xTg mice studied here show reductions in synaptic NMDA receptors at six months of age, presumably due to synapse-specific effects of Aβ. Reduction of STEP prevented this decrease in NMDA receptors and improved mouse behavior and electrophysiology. The authors suggest that this study makes STEP a target for therapies, and the fact that it affects a late stage of the disease process makes that suggestion exciting. There are no data from heterozygous STEP mice, which might more accurately reflect a situation of partial inhibition of STEP by drugs. Also, these types of genetic studies do not demonstrate what might happen if STEP is inhibited only after AD pathological changes begin, as would be...  Read more

Zhang et al. have published a very interesting study showing that deletion of the striatal-enriched tyrosine phosphatase (STEP) gene protects the 3xTg animal model of Alzheimer disease. The interesting part of this study is that the protection is not at the level of reducing Aβ or phospho-tau, but at the level of protecting neurons from synaptotoxic effects of AD pathological changes. The 3xTg mice studied here show reductions in synaptic NMDA receptors at six months of age, presumably due to synapse-specific effects of Aβ. Reduction of STEP prevented this decrease in NMDA receptors and improved mouse behavior and electrophysiology. The authors suggest that this study makes STEP a target for therapies, and the fact that it affects a late stage of the disease process makes that suggestion exciting. There are no data from heterozygous STEP mice, which might more accurately reflect a situation of partial inhibition of STEP by drugs. Also, these types of genetic studies do not demonstrate what might happen if STEP is inhibited only after AD pathological changes begin, as would be expected for any therapeutic approach. But in the end, it is exciting to see research moving beyond altering Aβ and tau, and toward the effects of these molecules on the brain.

View all comments by G. William Rebeck

The results described are surprising, and do not readily fit with the work from Mucke's group on fyn. It is also amazing how the loss of STEP corrects the behavioral impairment, without modifying the underlying pathology at all—at least at this early stage. It will be interesting to see what happens to older STEP crosses. Will pathology (amyloid deposits, tau accumulation in cells) proceed without change? Will the behavioral restoration continue as more florid pathology develops?

The fact that the STEP KO mice appear to have normal LTP (and no obvious impairment in other aspects of cognition) would seem to make STEP a good target for therapy, at least in the sense that it does not seem to be required for normal cognitive function in mice.

Given the effects of STEP KO on NMDA receptors, this is another surprise.

View all comments by Peter Davies