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

Accumulation of amyloid-β peptide (Aβ) in neuronal cells and in the extracellular regions in the brain is a major cause of Alzheimer’s disease (AD); therefore, inhibition of Aβ accumulation offers a promising approach for therapeutic strategies against AD. Aβ is produced by sequential proteolysis of amyloid precursor protein (APP) in late/recycling endosomes after endocytosis of APP located in the plasma membrane. Aβ 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 A-subunit, stimulated the transport of APP to the acidic compartment, which led to degradation of APP and a reduction in the amount of Aβ. mStx2a-treatment also inhibited the extracellular release of Aβ. Therefore, mStx2a may provide a new strategy to inhibit the production of Aβ by modulating the intracellular transport of APP. [Display omitted] •Amyloid precursor protein can be co-endocytosed with nontoxigenic Shiga toxin 2.•The toxin induces mistransport of amyloid precursor protein to lysosomes.•The mistransport causes the lysosomal degradation of amyloid precursor protein.•The degradation inhibits the production and the subsequent relase of amyloid-β.•The toxin treatment may protect against Alzheimer’s Disease caused by amyloid-β.