Tilting the scale towards degradation: CD147 stimulates extracellular degradation of Alzheimer's disease b-amyloid peptides

Editor's note: The Journal of Biological Chemistry has selected a paper from the Thinakaran and Sisodia labs as one of its "Papers of the Week" for the week of July 11. The following is a summary of the work.

Cerebral deposition of b-amyloid peptides (Ab) is a pathological hallmark of Alzheimer's disease. Ab is generated by sequential proteolysis of amyloid precursor protein (APP) by b- and g-secretases. The majority of Ab is secreted to the extracellular mileau, and a fraction of Ab is deposited in senile plaques. Secreted Ab can also be metabolized by extracellular amyloid degrading-enzymes such as the insulin-degrading enzyme and neprilysin. In addition, extracellular Ab can be cleared by cellular uptake coupled to lysosomal degradation. Thus, the extent of cerebral Ab deposition is governed by multiple factors that influence the delicate balance between Ab production and degradation.

In the July 11 issue of Journal of Biological Chemistry, Gopal Thinakaran and Sangram S. Sisodia report that CD147, a glycoprotein that stimulates production of matrix metalloproteinases, can also modulate extracellular A levels. The Editors of the Journal have selected their paper as a "paper of the week."

In a previous study, it was reported that CD147 regulated A production by functioning as a subunit of g-secretase. However, the authors of the new research found that CD147 levels and subcellular localization in cultured cells were quite different when compared to integral g-secretase subunits. Moreover, postnatal expression and distribution of CD147 in brain were also distinct from that of g-secretase subunits. Importantly, the authors found that while depletion of CD147 by siRNA inhibition increased extracellular Ab levels in intact cells, membranes isolated from CD147-depleted cells failed to elevate Ab production in an in vitro g-secretase assay. Thus, the authors concluded it is highly unlikely that CD147 functions as a -secretase subunit.

Instead, the authors found evidence for enhanced degradation of synthetic Ab in the medium conditioned by cells overexpressing CD147, suggesting the potential involvement of CD147-induced secreted forms of matrix metalloproteinases in modulating extracellular Ab levels.

Collectively, the collaborative research from the Thinakaran lab and Sisodia lab demonstrates that CD147 modulates Ab levels by stimulating extracellular degradation of Ab via mechanisms independent of A production.

Reference:

Vetrivel KS, Zhang X, Meckler X, Cheng H, Lee S, Gong P, Lopes KO, Chen Y, Iwata N, Yin KJ, Lee JM, Parent AT, Saido TC, Li YM, Sisodia SS, Thinakaran G. Evidence that CD147 modulation of A levels is mediated by extracellular degradation of secreted A . J Biol Chem. 2008 published online ahead of print May 5. PMID: 18456655

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Christian Hansel joins the Department of Neurobiology

It is a pleasure to welcome Dr. Christian Hansel to the Department of Neurobiology.

Dr. Hansel joins us after a very successful Assistant Professorship at Erasmus MC in the Netherlands, where he established himself as a leading figure in the study of plasticity in the cerebellum.

His arrival at the Department of Neurobiology follows shortly after David Freedman, formerly a post-doc with John Assad at Harvard, joined the department.

For more information

Christian Hansel Faculty page