Failure to support a genetic contribution of AKT1 polymorphisms and altered AKT signaling in schizophrenia

Department of Psychiatry, University of Tsukuba, Tsukuba, Ibaraki, Japan
Journal of Neurochemistry (Impact Factor: 4.28). 11/2006; 99(1):277-87. DOI: 10.1111/j.1471-4159.2006.04033.x
Source: PubMed


The protein kinase v-akt murine thymoma viral oncogene homolog (AKT) gene family comprises three human homologs that phosphorylate and inactivate glycogen synthase kinase 3beta (GSK3beta). Studies have reported the genetic association of AKT1 with schizophrenia. Additionally, decreased AKT1 protein expression and the reduced phosphorylation of GSK3beta were reported in this disease, leading to a new theory of attenuated AKT1-GSK3beta signaling in schizophrenia pathogenesis. We have evaluated this theory by performing both genetic and protein expression analyses. A family based association test of AKT1 did not show association with schizophrenia in Japanese subjects. The expression levels of total AKT, AKT1 and phosphorylated GSK3beta detected in the schizophrenic brains from two different brain banks also failed to support the theory. In addition, no attenuated AKT-GSK3beta signaling was observed in the lymphocytes from Japanese schizophrenics, contrasting with previous findings. Importantly, we found that the level of phosphorylated GSK3beta at Ser9 tended to be inversely correlated with postmortem intervals, and that the phosphorylation levels of AKT were inversely correlated with brain pH, issues not assessed in the previous study. These data introduce a note of caution when estimating the phosphorylation levels of GSK3beta and AKT in postmortem brains. Collectively, this study failed to support reduced signaling of the AKT-GSK3beta molecular cascade in schizophrenia.

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Available from: Kazuo Yamada
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    • "Recent studies have identified a number of genes associated with increased risk for developing schizophrenia (Consortium, 2008; Stefansson et al., 2008; Walsh et al., 2008). Among genetic factors, an association between schizophrenia and genetic variants for AKT1 has been reported in several studies of large family samples of European or Asian descent (Bajestan et al., 2006; Emamian et al., 2004; Ikeda et al., 2004; Schwab et al., 2005; Thiselton et al., 2008; Xu et al., 2007), although not all studies have measured this association (Ide et al., 2006; Liu et al., 2006; Ohtsuki et al., 2004; Turunen et al., 2007). Additional evidence emerges from decreased protein levels of the serine/threonine kinase Akt and levels of substrate phosphorylation reported in postmortem brain samples from some patients with schizophrenia (Emamian et al., 2004; Zhao et al., 2006). "
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    ABSTRACT: Genetic studies have associated deficient function of the serine/threonine kinase Akt1 with schizophrenia. This disorder is associated with developmental, structural, and functional abnormalities of the hippocampus that could be traced to abnormal Akt1 function. To establish a closer connection between Akt1 and hippocampal function, mice with a selective deletion of Akt1 (Akt1(-/-) mice) were examined for physiological and behavioral outcomes dependent on the hippocampus and associated with schizophrenia. Genetic deletion of Akt1 was associated with both impaired proliferative capacity of adult-born hippocampal progenitors and hippocampal long-term potentiation, indicating deficient functions of this brain region associated with neuroplasticity. Moreover, Akt1(-/-) mice demonstrated impairments in contextual fear conditioning and recall of spatial learning, behaviors known to selectively involve the hippocampus. Akt1(-/-) mice also showed reduced prepulse inhibition of the acoustic startle response, a sensorimotor gating response that is perturbed in schizophrenia. Postmortem tissue samples from patients with schizophrenia showed significant reductions of phosphorylated Akt levels in hilar neurons of the dentate gyrus, the neurogenic zone of the hippocampus. Taken together, these results implicate the Akt1 isoform in regulating hippocampal neuroplasticity and cognition and in contributing to the etiology of schizophrenia.
    Full-text · Article · Feb 2012 · Hippocampus
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    • "The additional multi-SNP haplotype analysis showed that specific haplotype is associated with lower Akt1 protein levels [20]. Controversial results have been issued for Japanese schizophrenic patients and Akt1 [15, 16, 21]. The detailed LD analysis from these Japanese studies suggested that there are two apparent LD blocks in the gene [21, 22]. "
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    ABSTRACT: A recent paper reported that Aβ oligomer causes neuronal cell death through the phosphatidylinositol-3-OH kinase (PI3K)-Akt-mTOR signaling pathway. Intraneuronal Aβ, a main pathological finding of Alzheimer's disease (AD), is also known as inhibiting activation of Akt. This study aims to investigate whether single nucleotide polymorphisms (SNPs) of the Akt1 gene are associated with AD. SNPs genotyped using TaqMan technology was analyzed using a case-control study design. Our case-control dataset consisted of 180 AD patients and 130 age-matched controls. Although two SNPs showed superficial positive, Hardy-Weinberg equilibrium (HWE) tests, and linkage disequilibrium (LD) analyses suggested that genetic regions of the gene are highly polymorphic. We failed to detect any synergetic association among Akt1 polymorphisms, Apolipoprotein E (APO E), and AD. Further genetic studies are needed to clarify the relationship between the Akt1 and AD.
    Full-text · Article · Jul 2011 · International Journal of Alzheimer's Disease
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    • " et al . 2004 ; Zhao et al . 2006 ) . These data suggest an increase in the GSK - 3 activity in schizophrenia . In contrast , other studies found reduced levels of GSK - 3β protein ( Beasley et al . 2001 ; Kozlovsky et al . 2000 ) coupled with reduced GSK - 3 activity ( Kozlovsky et al . 2001 ) and unchanged Akt concentration ( Amar et al . 2008 ; Ide et al . 2006 ) in the frontal cortex of patients with schizophrenia . Our data on decreased levels of Akt and GSK - 3 phosphorylation in NVHL animals are in agreement with the human studies suggesting increased GSK - 3 activity in schizophrenia . The elevated locomotor activity of NVHL animals may be due to enhanced GSK - 3 activity ( seen as reduce"
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    ABSTRACT: Animals with the neonatal ventral hippocampal lesion (NVHL) demonstrate altered responsiveness to stress and various drugs reminiscent of that in schizophrenia. Post-pubertal onset of abnormalities suggests the possibility of sex differences in NVHL effects that may model sex differences in schizophrenia. Here we demonstrate that novelty- and MK-801-induced hyperactivity is evident in both male and female NVHL rats, whereas only NVHL males were hyperactive in response to apomorphine. Next, we examined the sex- and NVHL-dependent differences in the activity of the ERK and Akt pathways. The basal activity of both pathways was higher in females than in males. NVHL reduces the level of phosphorylation of ERK1/2, Akt, and GSK-3 in both sexes, although males show more consistent down-regulation. Females had higher levels of G-protein-coupled kinases [G-protein-coupled receptor kinase (GRK)] 3 and 5, whereas the concentrations of other GRKs and arrestins were the same. In the nucleus accumbens, the concentration of GRK5 in females was elevated by NVHL to the male level. The data demonstrate profound sex differences in the expression and activity of signalling molecules that may underlie differential susceptibility to schizophrenia.
    Full-text · Article · Feb 2010 · The International Journal of Neuropsychopharmacology
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