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.
Department of Surgery, Royal Melbourne Hospital, University of Melbourne, Royal Parade, Parkville 3010, Victoria, Australia. niallmcorcoran@gmail.com
Niall M
NM
Corcoran
Daniel
D
Martin
Birgit
B
Hutter-Paier
Manfred
M
Windisch
Thanh
T
Nguyen
Lina
L
Nheu
Lars E
LE
Sundstrom
Anthony J
AJ
Costello
Christopher M
CM
Hovens
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