A nontoxigenic form of Shiga toxin 2 suppresses the production of amyloid 13 by altering the intracellular transport of amyloid precursor protein through its receptor-binding B-subunit

Accumulation of amyloid-13 peptide (A13) in neuronal cells and in the extracellular regions in the brain is a major cause of Alzheimer?s disease (AD); therefore, inhibition of A13 accumulation offers a promising approach for therapeutic strategies against AD. A13 is produced by sequential proteolysis of amyloid precursor protein (APP) in late/recycling endosomes after endocytosis of APP located in the plasma membrane. A13 is then released from cells in a free form or in an exosome-bound form. Shiga toxin (Stx) is a major virulence factor of enterohemorrhagic Escherichia coli. Recently, we found that one of the Stx subtypes, Stx2a, has a unique intracellular transport route after endocytosis through its receptor-binding B-subunit. A part of Stx2a can be transported to late/recycling endosomes and then degraded in a lysosomal acidic compartment, although in general Stx is transported to the Golgi and then to the endoplasmic reticulum in a retrograde manner. In this study, we found that treatment of APP-expressing cells with a mutant Stx2a (mStx2a), lacking cytotoxic activity because of mutations in the catalytic Asubunit, stimulated the transport of APP to the acidic compartment, which led to degradation of APP and a reduction in the amount of A13. mStx2a-treatment also inhibited the extracellular release of A13. Therefore, mStx2a may provide a new strategy to inhibit the production of A13 by modulating the intracellular transport of APP. ? 2021 The Authors. Published by Elsevier Inc. This is an open access article under the CC BY license

Automated summary

Accumulation of amyloid-13 peptide in neuronal cells and in the extracellular regions in the brain is a major cause of Alzheimer's disease. Inhibiting A13 accumulation provides a promising therapeutic strategy against AD by modulating the intracellular transport of APP.