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

Rebecca J Griffin; Aileen Moloney; Mary Kelliher; Janet A Johnston; Rivka Ravid; Peter Dockery; Rosemary O'Connor; Cora O'Neill

doi:10.1111/j.1471-4159.2004.02949.x

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

J Neurochem. 2005 Apr;93(1):105-17. doi: 10.1111/j.1471-4159.2004.02949.x.

Authors

Rebecca J Griffin¹, Aileen Moloney, Mary Kelliher, Janet A Johnston, Rivka Ravid, Peter Dockery, Rosemary O'Connor, Cora O'Neill

Affiliation

¹ Department of Biochemistry, BioSciences Institute, University College Cork, Cork, Ireland.

PMID: 15773910
DOI: 10.1111/j.1471-4159.2004.02949.x

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.

Publication types

Comparative Study
Research Support, Non-U.S. Gov't

MeSH terms

Aged
Aged, 80 and over
Alzheimer Disease / metabolism*
Alzheimer Disease / pathology
Antibodies, Monoclonal / metabolism
Blotting, Western / methods
Cerebral Cortex / metabolism
Cerebral Cortex / pathology
Cytosol / metabolism
Female
Glycogen Synthase Kinase 3 / metabolism
Glycogen Synthase Kinase 3 beta
Humans
Immunohistochemistry / methods
Male
Mental Status Schedule
Middle Aged
Neurofibrillary Tangles / metabolism
Neurofibrillary Tangles / pathology
Neurons / metabolism*
Neurons / pathology
PTEN Phosphohydrolase
Phosphoric Monoester Hydrolases / metabolism
Phosphorylation
Postmortem Changes
Protein Kinases / metabolism
Protein Serine-Threonine Kinases / metabolism*
Proto-Oncogene Proteins / metabolism*
Proto-Oncogene Proteins c-akt
Regression, Psychology
Serine / metabolism
TOR Serine-Threonine Kinases
Tumor Suppressor Proteins / metabolism
tau Proteins / metabolism

Substances

Antibodies, Monoclonal
PHF-1 monoclonal antibody
Proto-Oncogene Proteins
Tumor Suppressor Proteins
tau Proteins
Serine
Protein Kinases
MTOR protein, human
AKT1 protein, human
GSK3B protein, human
Glycogen Synthase Kinase 3 beta
Protein Serine-Threonine Kinases
Proto-Oncogene Proteins c-akt
TOR Serine-Threonine Kinases
Glycogen Synthase Kinase 3
Phosphoric Monoester Hydrolases
PTEN Phosphohydrolase
PTEN protein, human