title: Activation of Akt/PKB, increased phosphorylation of Akt substrates and loss and altered distribution of Akt and PTEN are features of Alzheimer's disease pathology.
abstract: Studies suggest that activation of phosphoinositide 3-kinase-Akt may protect against neuronal cell death in Alzheimer's disease (AD). Here, however, we provide evidence of increased Akt activation, and hyperphosphorylation of critical Akt substrates in AD brain, which link to AD pathogenesis, suggesting that treatments aiming to activate the pathway in AD need to be considered carefully. A different distribution of Akt and phospho-Akt was detected in AD temporal cortex neurons compared with control neurons, with increased levels of active phosphorylated-Akt in particulate fractions, and significant decreases in Akt levels in AD cytosolic fractions, causing increased activation of Akt (phosphorylated-Akt/total Akt ratio) in AD. In concordance, significant increases in the levels of phosphorylation of total Akt substrates, including: GSK3beta(Ser9), tau(Ser214), mTOR(Ser2448), and decreased levels of the Akt target, p27(kip1), were found in AD temporal cortex compared with controls. A significant loss and altered distribution of the major negative regulator of Akt, PTEN (phosphatase and tensin homologue deleted on chromosome 10), was also detected in AD neurons. Loss of phosphorylated-Akt and PTEN-containing neurons were found in hippocampal CA1 at end stages of AD. Taken together, these results support a potential role for aberrant control of Akt and PTEN signalling in AD.
authors.affiliation: Department of Biochemistry, BioSciences Institute, University College Cork, Cork, Ireland.
authors.forename: Rebecca J
authors.initials: RJ
authors.lastname: Griffin
authors.forename: Aileen
authors.initials: A
authors.lastname: Moloney
authors.forename: Mary
authors.initials: M
authors.lastname: Kelliher
authors.forename: Janet A
authors.initials: JA
authors.lastname: Johnston
authors.forename: Rivka
authors.initials: R
authors.lastname: Ravid
authors.forename: Peter
authors.initials: P
authors.lastname: Dockery
authors.forename: Rosemary
authors.initials: R
authors.lastname: O'Connor
authors.forename: Cora
authors.initials: C
authors.lastname: O'Neill
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000544:Alzheimer Disease / Q000378:metabolism* / Q000473:pathology; D000911:Antibodies, Monoclonal / Q000378:metabolism; D015153:Blotting, Western / Q000379:methods; D002540:Cerebral Cortex / Q000378:metabolism / Q000473:pathology; D003600:Cytosol / Q000378:metabolism; D005260:Female; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism; D000071679:Glycogen Synthase Kinase 3 beta; D006801:Humans; D007150:Immunohistochemistry / Q000379:methods; D008297:Male; D008609:Mental Status Schedule; D008875:Middle Aged; D016874:Neurofibrillary Tangles / Q000378:metabolism / Q000473:pathology; D009474:Neurons / Q000378:metabolism* / Q000473:pathology; D051059:PTEN Phosphohydrolase; D010744:Phosphoric Monoester Hydrolases / Q000378:metabolism; D010766:Phosphorylation; D011180:Postmortem Changes; D011494:Protein Kinases / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D011518:Proto-Oncogene Proteins / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt; D012043:Regression, Psychology; D012694:Serine / Q000378:metabolism; D058570:TOR Serine-Threonine Kinases; D025521:Tumor Suppressor Proteins / Q000378:metabolism; D016875:tau Proteins / Q000378:metabolism
chemical_list: D000911:Antibodies, Monoclonal; C085349:PHF-1 monoclonal antibody; D011518:Proto-Oncogene Proteins; D025521:Tumor Suppressor Proteins; D016875:tau Proteins; D012694:Serine; D011494:Protein Kinases; C546842:MTOR protein, human; C494918:AKT1 protein, human; C000605506:GSK3B protein, human; D000071679:Glycogen Synthase Kinase 3 beta; D017346:Protein Serine-Threonine Kinases; D051057:Proto-Oncogene Proteins c-akt; D058570:TOR Serine-Threonine Kinases; D038362:Glycogen Synthase Kinase 3; D010744:Phosphoric Monoester Hydrolases; D051059:PTEN Phosphohydrolase; C494929:PTEN protein, human