Schizophrenia Research Forum - A Catalyst for Creative Thinking
Home Profile Membership/Get Newsletter Log In Contact Us
 For Patients & Families
What's New
Recent Updates
SRF Papers
Current Papers
Search All Papers
Search Comments
News
Research News
Conference News
Plain English
Forums
Current Hypotheses
Idea Lab
Online Discussions
Virtual Conferences
Interviews
Resources
What We Know
SchizophreniaGene
Animal Models
Drugs in Trials
Research Tools
Grants
Jobs
Conferences
Journals
Community Calendar
General Information
Community
Member Directory
Researcher Profiles
Institutes and Labs
About the Site
Mission
History
SRF Team
Advisory Board
Support Us
How to Cite
Fan (E)Mail
The Schizophrenia Research Forum web site is sponsored by the Brain and Behavior Research Foundation and was created with funding from the U.S. National Institute of Mental Health.
Research News
back to News Search
Lithium Hinders Aβ Generation, Buffing Up GSK as Drug Target
View related comments: Alzheimer Research Forum
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

 
Submit a Comment on this News Article
Make a comment on this news article. 

If you already are a member, please login.
Not sure if you are a member? Search our member database.

*First Name  
*Last Name  
Affiliation  
Country or Territory  
*Login Email Address  
*Confirm Email Address  
*Password  
*Confirm Password  
Remember my Login and Password?  
Get SRF newsletter with recent commentary?  
 
Enter the code as it is shown below:
This code helps prevent automated registrations.

Please note: A member needs to be both registered and logged in to submit a comment.

Comment:

(If coauthors exist for this comment, please enter their names and email addresses at the end of the comment.)

References:


SRF News
SRF Comments
Text Size
Reset Text Size
Email this pageEmail this page

Share/Bookmark
Copyright © 2005- 2014 Schizophrenia Research Forum Privacy Policy Disclaimer Disclosure Copyright