This report on a connection between AKT-GSK3β signaling and schizophrenia provides evidence showing that schizophrenia and AD might have a common signaling cascade defect. Investigating the levels of AKT and Ser 9 phosphorylated GSK3β (pS9GSK3β) in the lymphocytes, and in hippocampal and frontal cortex tissue samples taken from schizophrenic patients, they found that AKT was downregulated and GSK3β activated.

GSK3β is a known tau kinase that, when activated in vitro and in vivo, leads to the formation of PHF-tau(1). In the case of AD, I assume that Aβ activates GSK3β by inhibiting the PI3 kinase cascade. Data from studies using cultured hippocampal tissue and animal models strongly support this(2-4). Furthermore, genetic studies revealed that the polymorphism of PI3K, which works upstream of AKT(5), may increase the risk of late-onset AD. Thus, the AKT-GSK3β signaling cascade may be involved in AD pathogenesis downstream of Aβ, contributing to NFT formation and the loss of synapses and neurons.

If, therefore, this signaling cascade is also impaired in schizophrenic...  Read more

This report on a connection between AKT-GSK3β signaling and schizophrenia provides evidence showing that schizophrenia and AD might have a common signaling cascade defect. Investigating the levels of AKT and Ser 9 phosphorylated GSK3β (pS9GSK3β) in the lymphocytes, and in hippocampal and frontal cortex tissue samples taken from schizophrenic patients, they found that AKT was downregulated and GSK3β activated.

GSK3β is a known tau kinase that, when activated in vitro and in vivo, leads to the formation of PHF-tau(1). In the case of AD, I assume that Aβ activates GSK3β by inhibiting the PI3 kinase cascade. Data from studies using cultured hippocampal tissue and animal models strongly support this(2-4). Furthermore, genetic studies revealed that the polymorphism of PI3K, which works upstream of AKT(5), may increase the risk of late-onset AD. Thus, the AKT-GSK3β signaling cascade may be involved in AD pathogenesis downstream of Aβ, contributing to NFT formation and the loss of synapses and neurons.

If, therefore, this signaling cascade is also impaired in schizophrenic patients, they might have a higher risk of developing AD. However, studies of schizophrenic patients have shown neither neurodegenerative pathology nor increased levels of CSF-tau compared to controls(6). This may be because haloperidol, a therapeutic drug for schizophrenia that activates AKT, probably inhibits GSK3β through that activation.

Hallucinations, the main schizophrenic phenotype, are often observed in AD. While the question remains which substrate of AKT and GSK3β is key to developing schizophrenia, the similarities between AD and schizophrenia with the AKT-GSK3β signaling cascade suggests that a GSK3 inhibitor might be a suitable therapeutic drug for these diseases.

References:
1. Sato, S. et al. Aberrant tau phosphorylation by glycogen synthase kinase-3beta and JNK3 induces oligomeric tau fibrils in COS-7 cells. J Biol Chem 277, 42060-5 (2002). Abstract

2. Takashima, A. et al. Exposure of rat hippocampal neurons to amyloid beta peptide (25-35) induces the inactivation of phosphatidyl inositol-3 kinase and the activation of tau protein kinase I/glycogen synthase kinase-3 beta. Neurosci Lett 203, 33-6 (1996). Abstract

3. Takashima, A. et al. Activation of tau protein kinase I/glycogen synthase kinase-3beta by amyloid beta peptide (25-35) enhances phosphorylation of tau in hippocampal neurons. Neurosci Res 31, 317-23 (1998). Abstract

4. Takashima, A., Noguchi, K., Sato, K., Hoshino, T. & Imahori, K. Tau protein kinase I is essential for amyloid beta-protein-induced neurotoxicity. Proc Natl Acad Sci U S A 90, 7789-93 (1993). Abstract

5. Liolitsa, D., Powell, J. & Lovestone, S. Genetic variability in the insulin signalling pathway may contribute to the risk of late onset Alzheimer's disease. J Neurol Neurosurg Psychiatry 73, 261-6 (2002). Abstract

6. Schonknecht, P. et al. Cerebrospinal fluid tau protein levels in schizophrenia. Eur Arch Psychiatry Clin Neurosci 253, 100-2 (2003). Abstract

View all comments by Akihiko Takashima

The findings by Emamian and colleagues provide advances in our understanding of the mechanisms underlying the pathophysiology of schizophrenia. However, many questions remain to be addressed:

1. How does an alteration in AKT1/GSK3β signaling contribute to schizophrenia, and what are the downstream targets of AKT1 that are likely to be involved?

2. It would be interesting to investigate changes in dopamine receptor density in the experiments with AKT1-/- mice, in order to correlate absence of AKT to dopamine, the up-front neurotransmitter in schizophrenia.

3. A key question is: What is the significance of reduced GSK3β at Ser9 in the absence of increase in the active GSK3β phosphorylated at Tyr216?

4. AKT is localized in the cytosol and also in mitochondria Bijur and Jope, 2003). Determining which of the cytosolic and/or mitochondrial pools of AKT are affected in schizophrenia is of considerable importance.

Interestingly, this study reinforces the hypothesis that AKT/GSK3 signaling pathways...  Read more

The findings by Emamian and colleagues provide advances in our understanding of the mechanisms underlying the pathophysiology of schizophrenia. However, many questions remain to be addressed:

1. How does an alteration in AKT1/GSK3β signaling contribute to schizophrenia, and what are the downstream targets of AKT1 that are likely to be involved?

2. It would be interesting to investigate changes in dopamine receptor density in the experiments with AKT1-/- mice, in order to correlate absence of AKT to dopamine, the up-front neurotransmitter in schizophrenia.

3. A key question is: What is the significance of reduced GSK3β at Ser9 in the absence of increase in the active GSK3β phosphorylated at Tyr216?

4. AKT is localized in the cytosol and also in mitochondria Bijur and Jope, 2003). Determining which of the cytosolic and/or mitochondrial pools of AKT are affected in schizophrenia is of considerable importance.

Interestingly, this study reinforces the hypothesis that AKT/GSK3 signaling pathways may be a common denominator underlying the pathophysiology of various neurological disorders, including Alzheimer’s disease. Cortex and hippocampus are the vulnerable areas in both schizophrenia and AD. In familial Alzheimer’s disease patients, AKT activity is markedly reduced in lymphoblast cells (Ryder et al., 2004), as is the case in lymphocytes in schizophrenic patients in this present study by Emamian et al. However, one noticeable difference is that a reduction in AKT is accompanied by an increase in GSK3β that may account for the presence of phosphorylated tau in AD (Ryder et al., 2004). It is worth emphasizing that AKT phosphorylates tau at the AT100 epitope, which represents a specific marker for Alzheimer’s disease paired helical filaments (Ksiezak-Reding et al., 2003). In this study of Emamian et al., an increase in GSK3β induced by haloperidol is consistent with a previous study showing that chronic treatment with neuroleptics significantly increases the development of neurofibrillary pathology in the brain of elderly schizophrenics (Wisniewski et al., 1994). It is not known whether the schizophrenic patients included in this study developed neurofibrillary pathology as evidenced by the presence of accumulated hyperphosphorylated tau. The ages of the patients also are not given in the report.

Thus, in addition to overlapping pathologies between Alzheimer’s and Parkinson’s diseases, schizophrenia may also share common overlapping pathways with these brain disorders, probably through AKT-GSK3β signaling. Thus, it is now of considerable importance to determine the significance of reduced GSK3 pSer9 in schizophrenic patients in the absence of an increase in the active GSK3 pTyr216, a process that is suggested to phosphorylate tau in Alzheimer’s disease.

References:
Bijur GN, Jope RS. Rapid accumulation of Akt in mitochondria following phosphatidylinositol 3-kinase activation. J Neurochem. 2003 Dec;87(6):1427-35. Abstract

Ryder J, Su Y, Ni B. Akt/GSK3beta serine/threonine kinases: evidence for a signalling pathway mediated by familial Alzheimer's disease mutations. Cell Signal. 2004 Feb;16(2):187-200. Abstract

Ksiezak-Reding H, Pyo HK, Feinstein B, Pasinetti GM. Akt/PKB kinase phosphorylates separately Thr212 and Ser214 of tau protein in vitro. Biochim Biophys Acta. 2003 Nov 20;1639(3):159-68. Abstract

Wisniewski HM, Constantinidis J, Wegiel J, Bobinski M, Tarnawski M. Neurofibrillary pathology in brains of elderly schizophrenics treated with neuroleptics. Alzheimer Dis Assoc Disord. 1994 Winter;8(4):211-27. Abstract

View all comments by Othman Ghribi