Alzheimer's researchers sneak regular peeks over the shoulders of colleagues working on Parkinson's and other neurodegenerative diseases. Why not do the same with schizophrenia researchers, who are working in a disease that features hallucinations—an occasional feature of AD—and obvious deficits in working memory? Here, then, is such a peek: A paper in Nature Genetics, wherein researchers implicate impaired signaling in the AKT1-GSK3β pathway in schizophrenia.

The tauophiles in the Alzheimer's research community have a longstanding interest in glycogen synthase kinase (GSK)3β because it is known to phosphorylate tau (see ARF related news story), and those more drawn to the amyloid camp have also begun to show interest in the GSK3α variant, which could be involved in the production of Aβ (see ARF related news story). GSK3β is well-studied due to its role in regulating insulin and β-catenin in the Wnt pathway.

The major factor controlling GSK3β activation is the protein-serine/threonine kinase AKT1, which has already come to interest AD researchers for its role in inhibiting apoptosis. And the researchers have been quick to note that AKT1 mediates phoshatidylinositol 3 (PI3) kinase signaling, which in turn is susceptible to Aβ control. Psychiatric disease researchers have turned their attention to AKT1, which appears to be a principal target of lithium and other drugs used in bipolar disorder. There is some evidence that the AKT gene increases risk for bipolar disorder. Given the evidence for overlapping genetic and biochemical abnormalities in bipolar disorder and schizophrenia, AKT1 is also of great interest in schizophrenia research.

In the current study, a multi-institutional team led by Joseph Gogos of Columbia University and Maria Karayiorgou of the Rockefeller University, both in New York City, went on an interesting "fishing expedition." They write, "We speculated that alterations in brain levels or activity of protein kinases and phosphatases may contribute to schizophrenia susceptibility in humans and that this might be observed in the peripheral tissues of individuals with schizophrenia." Assessing protein levels in peripheral blood lymphocytes, they focused on kinases implicated in synaptic plasticity, and were rewarded with the finding that levels of AKT1 protein were 68 percent lower in subjects with schizophrenia (P = 0.014). This went hand-in-hand with significant decreases in phosphorylation of the AKT1 target GSK3β both in peripheral lymphocytes and in postmortem tissue from frontal cortex of schizophrenia patients. In addition, AKT1 levels were reduced in the cortex of patients.

The site of the AKT1 gene, in the cytogenetic band 14q32, has never been fingered as a susceptibility locus in linkage scans of kindreds with schizophrenia. However, the authors found a significant association between schizophrenia and a haplotype of the AKT1 gene associated with lower protein levels. In another experiment, the authors turned to AKT1 -/- mice to investigate whether these show any abnormalities that might be relevant to schizophrenia. They indeed found that this knockout strain produced deficits in a measure of sensorimotor gating, a defect characteristic of schizophrenia. In addition, the authors showed in-vivo evidence that haloperidol, much like lithium, boosts phosphorylation of AKT1, evidence that the AKT1-GSK3β pathway could be a prime site of action for the antipsychotic medication.

As catalogued by the authors, AKT1 turns up as a player in many cellular processes, with links to important molecules (e.g., GABRA, BDNF, NRATC, calcineurin, neuregulin), and thus is poised to have wide influence. "This influence may be additive, perhaps due to small impairment of several processes, or may be restricted to a small number of key processes that are particularly AKT1 dosage-dependent. In any case, our data is consistent with a model in which impairment of AKT1-GSK3β signaling increases the liability of these neuronal circuits to additional genetic or environmental insults that ultimately lead to the disease," the authors conclude.—Hakon Heimer


  1. 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.


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  2. 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.


    . Rapid accumulation of Akt in mitochondria following phosphatidylinositol 3-kinase activation. J Neurochem. 2003 Dec;87(6):1427-35. PubMed.

    . 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. PubMed.

    . Akt/PKB kinase phosphorylates separately Thr212 and Ser214 of tau protein in vitro. Biochim Biophys Acta. 2003 Nov 20;1639(3):159-68. PubMed.

    . Neurofibrillary pathology in brains of elderly schizophrenics treated with neuroleptics. Alzheimer Dis Assoc Disord. 1994 Winter;8(4):211-27. PubMed.

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News Citations

  1. Wingless Pathway Helps Tauopathy Take Off
  2. Lithium Hinders Aβ Generation, Buffing Up GSK as Drug Target

Further Reading

Primary Papers

  1. . Convergent evidence for impaired AKT1-GSK3beta signaling in schizophrenia. Nat Genet. 2004 Feb;36(2):131-7. PubMed.