Sodium selenate specifically activates PP2A phosphatase, dephosphorylates tau and reverses memory deficits in an Alzheimer's disease model.
Neurofibrillary tangles composed of abnormally hyperphosphorylated tau protein are a hallmark of Alzheimer's disease (AD) and related tauopathies. Tau hyperphosphorylation is thought to promote aggregation with subsequent tangle formation. Reducing tau phosphorylation by boosting the activity of the key phosphatase/s that mediate dephosphorylation of tau could be a viable clinical strategy in AD. One of the key phosphatases implicated in regulating tau protein phosphorylation is the serine-threonine phosphatase PP2A. We have determined that sodium selenate can act as a specific agonist for PP2A, significantly boosting phosphatase activity. Acute treatment of either neuroblastoma cells or normal aged mice with sodium selenate rapidly reduced tau protein phosphorylation. Sodium selenate-treated transgenic TAU441 mice had significantly lower levels of phospho- and total tau levels in the hippocampus and amygdala compared with controls and exhibited significantly improved spatial learning and memory on the Morris Water Maze task. Sodium selenate is a specific activator of PP2A with excellent oral bioavailability, and favourable central nervous system penetrating properties. Clinical studies in patients with AD are envisaged in the near future.
Corcoran
Niall M
NM
Department of Surgery, Royal Melbourne Hospital, University of Melbourne, Royal Parade, Parkville 3010, Victoria, Australia. niallmcorcoran@gmail.com
Martin
Daniel
D
Hutter-Paier
Birgit
B
Windisch
Manfred
M
Nguyen
Thanh
T
Nheu
Lina
L
Sundstrom
Lars E
LE
Costello
Anthony J
AJ
Hovens
Christopher M
CM
D000544:Alzheimer Disease / Q000188:drug therapy / Q000378:metabolism* / Q000503:physiopathology*; D000704:Analysis of Variance; D000818:Animals; D015153:Blotting, Western; D045744:Cell Line, Tumor; D002478:Cells, Cultured; D004195:Disease Models, Animal; D006624:Hippocampus / Q000378:metabolism; D006801:Humans; D007150:Immunohistochemistry; D047468:Immunoprecipitation; D018782:Maze Learning / Q000187:drug effects*; D008569:Memory Disorders / Q000188:drug therapy / Q000378:metabolism / Q000503:physiopathology; D051379:Mice; D008822:Mice, Transgenic; D009924:Organ Culture Techniques; D010766:Phosphorylation / Q000187:drug effects; D054648:Protein Phosphatase 2 / Q000378:metabolism*; D051381:Rats; D017208:Rats, Wistar; D045442:Rotarod Performance Test; D064586:Selenic Acid; D018036:Selenium Compounds / Q000008:administration & dosage*; D016875:tau Proteins / Q000378:metabolism*
D018036:Selenium Compounds; D016875:tau Proteins; D054648:Protein Phosphatase 2; D064586:Selenic Acid