APP E590D mutation increases generation of Aβ and Aη peptides and exacerbates tauopathy

Accumulation of Amyloid β (Aβ), a peptide derived from endocytic processing of the amyloid precursor protein (APP), is a critical initial step in the development of Alzheimer's disease (AD). While the APP695^E590D mutation was previously discovered in 2 pathologically confirmed AD patients, the pathogenicity of this mutation has remained uncertain due to its exceptional rarity. Here, we characterize the APP695^E590D mutation by evaluating multiple APP metabolites and determining its effects on tauopathy in cellular and animal models. We show that APP695^E590D not only increases Aβ through endocytic β-secretase processing but also increases Aη, an alternative APP-derived synaptotoxic peptide. We further demonstrate that APP695^E590D promotes tauopathy by increasing tau seeding and aggregation in cellular models and exacerbating phospho-tau pathology and neuroinflammation in tau^P301S mice. These results reveal a unique modality by which APP695^E590D impinges on AD pathology by enhancing both Aβ and Aη generation and accelerating tauopathy.