Genetic reduction of striatal-enriched tyrosine phosphatase (STEP) reverses cognitive and cellular deficits in an Alzheimer's disease mouse model.
Alzheimer's disease (AD) is a progressive and incurable neurodegenerative disorder. Early in the pathophysiology of AD, synaptic function is disrupted by soluble Aβ oligomers, possibly through Aβ-mediated internalization of NMDA receptors. Striatal-enriched phosphatase (STEP) is a tyrosine phosphatase that regulates the internalization of NMDA receptors. Recent work shows that STEP is elevated in the prefrontal cortex of human AD patients and in animal models of AD. Here, we use genetic manipulations to reduce STEP activity in a triple transgenic AD mouse model and show that a decrease in STEP levels reverses cognitive and cellular deficits observed in these mice. Our results suggest that STEP inhibitors may prove therapeutic for this devastating disorder.
Zhang
Yongfang
Y
Child Study Center, Yale University School of Medicine, New Haven, CT 06520, USA.
Kurup
Pradeep
P
Xu
Jian
J
Carty
Nikisha
N
Fernandez
Stephanie M
SM
Nygaard
Haakon B
HB
Pittenger
Christopher
C
Greengard
Paul
P
Strittmatter
Stephen M
SM
Nairn
Angus C
AC
Lombroso
Paul J
PJ
D000544:Alzheimer Disease / Q000188:drug therapy / Q000201:enzymology* / Q000235:genetics / Q000473:pathology; D016564:Amyloid beta-Protein Precursor / Q000235:genetics / Q000378:metabolism; D000818:Animals; D002540:Cerebral Cortex / Q000201:enzymology* / Q000473:pathology; D004195:Disease Models, Animal; D004791:Enzyme Inhibitors / Q000627:therapeutic use; D006801:Humans; D051379:Mice; D008822:Mice, Transgenic; D054558:Protein Tyrosine Phosphatases, Non-Receptor / Q000037:antagonists & inhibitors / Q000378:metabolism*; D016194:Receptors, N-Methyl-D-Aspartate / Q000235:genetics / Q000378:metabolism
C545487:APP protein, human; D016564:Amyloid beta-Protein Precursor; D004791:Enzyme Inhibitors; D016194:Receptors, N-Methyl-D-Aspartate; D054558:Protein Tyrosine Phosphatases, Non-Receptor; C082101:Ptpn5 protein, mouse