Year: 2026
Type: article
Abstract: 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.
Source: npj Dementia
Authors: Tian Liu, Liam Wetzel, David Roy, Kexin Zhang, Zexi Zhu, Pavan Kumaraguru, Viraj Gorthi, Hanna Jeon, Jung-A A. Woo, David E. Kang
Language: English
Subfield: Physiology
Field: Medicine
Domain: Health Sciences
Open Access status: hybrid
Awards: G1360370882, G2622865600, Targeting CHCHD10 to mitigate Alzheimer's disease pathogenesis, G4390231255, Decoding the BETA-arrestin2-LMBRD2 cascade in ALPHA-synuclein pathogenesis., Protective Role of Mitochondrial CHCHD10 in Alzheimer's Disease through MAM and Mitophagy Mechanisms., Deubiquitinase USP19 in TDP-43 pathogenesis., G9000013058, G9000056371, G9000067567, G9000266261, Pathogenic Role of APP E590D in Alzheimer’s Disease., Deubiquitinase USP19 in TDP-43 pathogenesis.
OpenAlex ID: W7134287240