19 February 2004. Amyloid-β precursor protein (AβPP) has gained a notorious reputation because it releases the Aβ peptide that gums up intraneuronal spaces in Alzheimer's brains. Like many of notoriety, however, AβPP probably has a good side, as well, because without one, evolution would have done away with this gene. The beneficial function of AβPP has remained somewhat mysterious, but its similarities to the structure and processing of the cell surface receptor Notch suggest that it may convey extracellular signals to the nucleus (see related ARF Live Discussion). There is evidence to support this view, not least that the intracellular domains of AβPP are transcriptional activators (see ARF related news story). But if true, then there must be an extracellular AβPP ligand, or ligands, waiting to be discovered. In the February 24 PNAS, Angela Ho and Thomas Sudhof at the University of Texas Southwestern Medical Center, Dallas, report that F-spondin may be one such ligand. The paper is currently available online.
Ho used an affinity purification method to capture proteins that bind to AβPP. From a mixture of such proteins, she identified F-spondin as a major component. The reverse experiment, using the spondin on the column, captured AβPP, suggesting that the interaction is more than fortuitous. By performing this experiment with specific parts of the proteins, Ho was able to show that the N-terminal reelin and the central spondin domains of F-spondin, and the central extracellular domain of AβPP are all essential for binding.
To test if the binding has any physiological consequence, Ho transfected an F-spondin expression plasmid into HEK cells that produce AβPP and β-secretase (BACE). As judged by the amount of C-terminal fragments produced by the cells, the spondin dramatically inhibited the β-secretase in a dose-dependent manner. Furthermore, F-spondin also inhibited activation of a reporter gene by AβPP.
Overall, the experiments suggest that F-spondin can reduce β-secretase cleavage of AβPP, the first of two proteolytic steps that are required to release Aβ. Thus, these experiments may open up an avenue for potential therapeutics, the authors suggest, adding that they have licensed intellectual property arising from this work to a biotechnology company.—Tom Fagan
Ho A, Sudhof TC. Binding of F-spondin to amyloid-β precursor protein: a candidate amyloid-beta precursor protein ligand that modulates amyloid- beta precursor protein cleavage. PNAS Feb. 24 2004;101:2548-2553. Abstract