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 APP695E590D 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 APP695E590D mutation by evaluating multiple APP metabolites and determining its effects on tauopathy in cellular and animal models. We show that APP695E590D not only increases Aβ through endocytic β-secretase processing but also increases Aη, an alternative APP-derived synaptotoxic peptide. We further demonstrate that APP695E590D promotes tauopathy by increasing tau seeding and aggregation in cellular models and exacerbating phospho-tau pathology and neuroinflammation in tauP301S mice. These results reveal a unique modality by which APP695E590D impinges on AD pathology by enhancing both Aβ and Aη generation and accelerating tauopathy.