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Lithium Hinders Aβ Generation, Buffing Up GSK as Drug Target

Article appears by special arrangement with Alzheimer Research Forum. See original article with additional links/commentary.

22 May 2003. The widely used psychiatric drug lithium, and other agents that inhibit glycogen synthase kinase-3 (GSK3), have been mentioned as possible Alzheimer's disease therapies for some time, primarily because GSK3 is one of several kinases known to phosphorylate tau. An article in today's Nature reinforces more recent speculation that interfering with GSK3 could also reduce the production of the Aβ peptide, putting before drug developers the tantalizing prospect of hitting two birds (i.e., the two major AD pathologies) with one stone.

The suggestion that GSK3 could be involved in Aβ production stems from the kinase's interaction with presenilins, though there has been no demonstration of direct involvement of GSK3 in presenilin-mediated γ-secretase cleavage of amyloid precursor protein. Last year, Akihiko Takashima's group reported that high doses of the GSK3 inhibitor lithium interfere with in-vitro production of Aβ40 and 42 (Sun et al., 2002). The current report by Peter Klein and associates at the University of Pennsylvania in Philadelphia confirms and extends this finding, showing that more clinically relevant doses of lithium chloride reduce Aβ production from full-length APP in cultured neurons, as well as in the brains of a mouse model transgenic for mutated APP and containing a "knock-in" of a presenilin mutation. Klein and colleagues also identified the target of lithium responsible for this effect, namely GSK3α. The fact that C-terminal fragments of AβPP pile up in the in-vitro models indicates that this effect of lithium occurs before or during the γ-secretase cleavage of AβPP. Inhibitor experiments in AβPP-transgenic CHO cells using kenpaullone (which inhibits GSK and, less strongly, CDKs) and roscovitine (which inhibits CDKs but not GSK), indicated that lithium inhibits Aβ generation via GSK inhibition, not via CDK inhibition.

The researchers provide several lines of evidence to show that it is the GSK3α isoform—and not GSK3β—that facilitates Aβ production. For example, RNAi-mediated depletion of GSK3α, but not β, reduces Aβ production. Conversely, moderate overexpression of the α isoform increases Aβ production.

Unlike most γ-secretase inhibitors, lithium did not inhibit Notch processing by γ-secretase. This would be an important specificity criteria for a drug candidate. The researchers suspect that GSKα might specifically regulate γ-secretase activity toward AβPP, or access of AβPP to the enzyme complex. NSAIDs that modulate γ-secretase activity also do not affect Notch cleavage (see Alzheimer Research Forum related news story), though they appear to act by a different mechanism.

Lithium targets both the α and β isoforms, making an agent that targets only GSK3α preferable, write the authors. In an accompanying News and Views article, Bart de Strooper of KU Leuven, Belgium, and James Woodgett at Ontario Cancer Institute in Toronto add that GSK inhibition might carry the risk of tumor-causing side effects through the GSK target β-catenin. Lithium itself is not associated with increased risk of cancer, but new, more potent GSK-3 inhibitors might, so it is important to keep that possibility in mind, noted Klein. On the up side, however, de Strooper and Woodgett write that the effective dose of lithium chloride in the present experiments falls within the range of the accepted therapeutic dose for this drug. They write that some Alzheimer's patients might benefit from lithium, but recommend that any potential effect of this drug on dementia be assessed in a clinical trial designed for that purpose, since measuring this outcome in psychiatric patients who currently receive this drug will be difficult.—Hakon Heimer and Gabrielle Strobel (Alzheimer Research Forum).

References:
Phiel CJ, Wilson CA, Lee VM-Y, Klein PS. GSK3a regulates production of Alzheimer's disease amyloid-b peptides. Nature. 2003 May 22;423:435-9. Abstract

De Strooper B, Woodgett J. Mental Plaque Removal. Nature. 2003 May 22;423. Abstract

Comments on Related News


Related News: WCPG 2005: SELENBP1 Joins Array of Schizophrenia Gene Candidates

Comment by:  Mary Reid
Submitted 21 October 2005
Posted 21 October 2005

The study by Ming Tsuang and colleagues reporting increased SELENBP1 in schizophrenia is very interesting. Might that result in reduced function of the recently described anti-inflammatory gene selenoprotein S on chromosome 15 (1)? Curran et al. report that suppression of SEPS1 results in increased release of TNFα and Il-6. Gilmore et al. (2) report that cytokines generated in response to infection, IL-1β, TNFα, and IL-6 can significantly reduce dendrite development and complexity of developing cortical neurons, consistent with the neuropathology of schizophrenia.

References:
1. Curran JE, Jowett JB, Elliott KS, Gao Y, Gluschenko K, Wang J, Azim DM, Cai G, Mahaney MC, Comuzzie AG, Dyer TD, Walder KR, Zimmet P, Maccluer JW, Collier GR, Kissebah AH, Blangero J. Genetic variation in selenoprotein S influences inflammatory response. Nat Genet. 2005 Oct 9; [Epub ahead of print] Abstract

2. Gilmore JH, Fredrik Jarskog L, Vadlamudi S, Lauder JM. Prenatal Infection and Risk for Schizophrenia: IL-1beta, IL-6, and TNFalpha Inhibit Cortical Neuron Dendrite Development. Neuropsychopharmacology. 2004 Jul;29(7):1221-9. Abstract

View all comments by Mary Reid

Related News: WCPG 2005: SELENBP1 Joins Array of Schizophrenia Gene Candidates

Comment by:  Mary Reid
Submitted 21 October 2005
Posted 21 October 2005

I wonder whether the study by Ishida et al. (1) finding that acetaminophen cytotoxicity is enhanced in selenium-binding protein-overexpressed COS-1 cells may help explain the results reported by the Mortensen group in two separate studies. In one, they find that mothers who take aspirin and acetaminophen during the second trimester have a fourfold risk of giving birth to a child who later develops schizophrenia as an adult (2). In the other, they report an increased risk of schizophrenia following paracetamol poisoning (3). It would seem that should SELENBP1 be a valid marker for the diagnosis of schizophrenia, then paracetamol would be contraindicated.

A further study by Ishida and colleagues (4) reports induction of hepatic selenium-binding protein by aryl hydrocarbon receptor ligands in rats. Does this suggest that AHR ligands such as polycyclic aromatic hydrocarbons and polychlorinated dioxin compounds may cause schizophrenia? Does this explain the reports of schizophrenia in the Vietnam veterans?

References:
1. Ishida T, Abe M, Oguri K, Yamada H. Enhancement of acetaminophen cytotoxicity in selenium-binding protein-overexpressed COS-1 cells. Drug Metab Pharmacokinet. 2004 Aug;19(4):290-6. Abstract

2. Sorensen HJ, Mortensen EL, Reinisch JM, Mednick SA. Association between prenatal exposure to analgesics and risk of schizophrenia. Br J Psychiatry. 2004 Nov;185:366-71. Abstract

3. Jepsen P, Qin P, Norgard B, Agerbo E, Mortensen PB, Vilstrup H, Sorensen HT. The association between admission for poisoning with paracetamol or other weak analgesics and subsequent admission for psychiatric disorder: a Danish nationwide case-control study. Aliment Pharmacol Ther. 2005 Oct 1;22(7):645-51. Abstract

4. Ishida, T., Ishii, Y., Yamada, H., and Oguri, K. The induction of hepatic selenium-binding protein by aryl hydrocarbon (Ah)-receptor ligands in rats. J. Health Sci., 48: 62-68, 2002.

View all comments by Mary Reid

Related News: WCPG 2005: SELENBP1 Joins Array of Schizophrenia Gene Candidates

Comment by:  Stephen J. Glatt
Submitted 25 October 2005
Posted 25 October 2005
  I recommend the Primary Papers

Response to comment by Mary Reid posted 21 October 2005
I wish we knew more of the function of SELENBP1, other than the fact that it binds selenium. Does it sequester it, thus making it unavailable for biological activity, or is it a transporter or receptor for selenium, making it more active/available? Unfortunately, the ontology of the gene is poorly documented. One distinct possibility is that the role of the gene/protein is better understood, but under a pseudonym, such as heat shock protein 56 (HSP56). We need to do more reading into this possibility to determine what the role of the protein is, but we do know that it is expressed in the growing tips of neurites.

View all comments by Stephen J. Glatt

Related News: WCPG 2005: SELENBP1 Joins Array of Schizophrenia Gene Candidates

Comment by:  Stephen J. Glatt
Submitted 25 October 2005
Posted 26 October 2005
  I recommend the Primary Papers

Response to comment by Karoly Mirnics posted 21 October 2005
Replication will be key, and we hope that others will utilize gene expression microarrays to search for potential schizophrenia biomarkers as we have done. Our findings of dysregulation of specific myelin-related genes are consistent with prior work, as is the energy pathway dysfunction. Our work in conjunction with the others is painting a consistent picture of dysfunction in schizophrenia.

View all comments by Stephen J. Glatt

Related News: WCPG 2005: SELENBP1 Joins Array of Schizophrenia Gene Candidates

Comment by:  Mary Reid
Submitted 26 October 2005
Posted 26 October 2005

It certainly will be of interest to see further studies regarding the function of SELENBP1. Porat et al. find that 56SBP participates in late-stage intra-Golgi transport, but suggest that it may have more than one physiological role. The authors propose that SBP56 is active downstream of the Rab proteins. Might it be worthwhile to look at Rab36-22q11.2? A study by Mori et al. localized Rab36 at the Golgi body, suggesting that it is involved in vesicular transport around the Golgi apparatus.

References:
Porat A, Sagiv Y, Elazar Z. A 56-kDa selenium-binding protein participates in intra-Golgi protein transport. J Biol Chem. 2000 May 12;275(19):14457-65. Abstract

Mori T, Fukuda Y, Kuroda H, Matsumura T, Ota S, Sugimoto T, Nakamura Y, Inazawa J. Cloning and characterization of a novel Rab-family gene, Rab36, within the region at 22q11.2 that is homozygously deleted in malignant rhabdoid tumors. Biochem Biophys Res Commun. 1999 Jan 27;254(3):594-600. Abstract

View all comments by Mary Reid

Related News: WCPG 2005: SELENBP1 Joins Array of Schizophrenia Gene Candidates

Comment by:  Caroline GraffToru Kimura
Submitted 3 November 2005
Posted 3 November 2005

The paper by Glatt and coworkers reports on the gene expression differences in postmortem brain samples from individuals with schizophrenia and nonpsychiatric control samples. The researchers then compared these profiles with expression differences observed in blood from a separate sample of schizophrenic and nonpsychiatric controls.

Since there is no gold standard for the statistical evaluation of microarray data analysis, many alternative methods have been reported. In this study, Glatt et al. adopted their original method termed CORGON. One of the features of their method is treatment of noise. They assumed multiplicative rather than additive noise. Though it is difficult to evaluate the possible advantageous effect of assuming multiplicative rather than additive noise on the data set presented, analytical models which assume that the error of the observed expression signals of microarray is multiplicative have been well studied recently. Multiplicative models appear to be more suitable than simple additive models, at least for some microarray data sets. The permutation test used to identify differentially expressed genes is not dependent on typical distributions used in general statistical analyses, but based on the distribution generated from observed values. It may be contradictory that they used the t-statistic in order to compare each permutation with the absolute value for unpermuted t-statistic, because it is well known that the statistic assuming univariate normal distribution, such as the t- statistic, shows poor sensitivity in detecting qualitatively consistent changes when it shows large quantitative variability. It is not clear if this problem can be avoided by using log expression values, which were adopted in this study.

It is exciting that SELENBP1 was discovered as a candidate biomarker for schizophrenia in common with both brain and blood. One of the issues to be validated is the reproducibility of the data by independent samples. The authors used blood samples to compare expression changes with brain samples, and found that six genes showed differential expression between cases and controls in these two apparently unrelated tissues. Perhaps one needs to be cautious, however, in the interpretation of these findings, since only one, SELENBP1, showed change in the same direction. It is not obvious how such expression changes in opposite directions reflect a common biological mechanism. The authors also demonstrated differential SELENBP1 protein expression in brain; however, being such a small (1.16-fold) mRNA expression difference, it is difficult to draw any conclusions about a possible correlation. Further, as shown in Figure 1 of the paper, the SELENBP1 staining was increased in glia, whereas the protein was decreased in neurons in schizophrenic brain compared with controls.

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View all comments by Toru Kimura

Related News: WCPG 2005: SELENBP1 Joins Array of Schizophrenia Gene Candidates

Comment by:  Stephen J. Glatt
Submitted 7 November 2005
Posted 7 November 2005

Response to comment by Graff and Kimura
We agree that it is not obvious how such expression changes in opposite directions reflect a common biological mechanism. This is precisely why we focused our subsequent efforts on SELENBP1. It is also important to realize that perhaps many more genes had corresponding differential expression in the blood and brain, but we may not have detected them due to the highly conservative nature of our statistical analyses.

We would also underscore that we don't know what fold-change difference between groups is biologically meaningful, which is why we focus on the significance level instead. The change in SELENBP1 may not be large, but it seems to be highly reliable. Replication efforts should prove very helpful in establishing the utility of SELENBP1 to identify schizophrenia.

View all comments by Stephen J. Glatt