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Interaction of two genes possibly involved in the regulation of the amyloid precursor protein (APP) processing

Molecular Psychiatry volume 5, pages 240–241 (2000)Cite this article

SIR – An intronic polymorphism of the gene encoding the transmembrane protein presenilin 1 (PS1) was found to be associated with increased risk for sporadic AD (ie over-representation of allele 1 in AD),1 however, this observation has been challenged by subsequent studies. These inconsistent findings might result from interactions of PS1 with other susceptibility genes and their products. Recently, Xia et al2 identified PS1 to be crucial for the catalytic activity of the γ-secretase, which is one of the two yet unidentified proteases (β- and γ-secretase) responsible for cleavage of the amyloid precursor protein (APP) into amyloidogenic components (βA4).

Cathepsin D (catD), an acid protease active in intracellular protein breakdown, has in vitro β- and γ-secretase-like properties and has also been implicated in the pathogenesis of AD. An exonic polymorphism of the catD gene (allele T) was recently found to be a major risk factor for the development of sporadic AD.3 Wolfe et al4 proposed that γ-secretase is an aspartyl protease with properties similar to those of cathepsin D. Thus, both genetic and biochemical data suggest an involvement of PS1 and catD in the cleavage and further processing of APP. Given this evidence, we hypothesised that genetic interactions between PS1 and catD would modify the risk for the development of sporadic AD and might be responsible for the conflicting reports on the association of the PS1 genotype with AD.

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References

  1. Wragg M et al. Lancet 1996; 347: 509–512

  2. Xia W et al. Biochemistry 1998; 37: 16465–16471

  3. Papassotiropoulos A et al. Neurosci Lett 1999; 262: 171–174

  4. Wolfe MS et al. Biochemistry 1999; 38: 4720–4727

  5. Touitou I et al. Eur J Cancer 1994; 30A: 390–394

  6. Chevallier N et al. Brain Res 1997; 750: 11–19

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Acknowledgements

The study was supported by the BONFOR grants program of the Medical Faculty of the University of Bonn (AP 111/34) and the Deutsche Forschungsgemeinschaft (He 2318).

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Authors and Affiliations

  1. Department of Psychiatry, University of Bonn, Germany

    A Papassotiropoulos, M Bagli, F Jessen, W Maier & R Heun

  2. Department of Psychiatry, Technische Univer sitaet Muenchen, Germany

    H Förstl & A Kurz

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  1. A Papassotiropoulos
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  2. M Bagli
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  3. F Jessen
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  4. W Maier
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  5. H Förstl
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  6. A Kurz
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  7. R Heun
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Correspondence to A Papassotiropoulos.

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Papassotiropoulos, A., Bagli, M., Jessen, F. et al. Interaction of two genes possibly involved in the regulation of the amyloid precursor protein (APP) processing. Mol Psychiatry 5, 240–241 (2000). https://doi.org/10.1038/sj.mp.4000699

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