E674Q (Shanghai mutant), a novel amyloid precursor protein mutation, in familial late-onset Alzheimer's disease.

Identified as the pathogenic genes of Alzheimer's disease (AD), , , mainly lead to early-onset AD, whose course is more aggressive, and atypical symptoms are more common than sporadic AD. Here, a novel missense mutation, E674Q (also named "Shanghai "), was detected in a Chinese index patient with typical late-onset AD (LOAD) who developed memory decline in his mid-70s. The results from neuroimaging were consistent with AD, where widespread amyloid β deposition was demonstrated in F-florbetapir Positron Emission Tomography (PET). E674Q is close to the β-secretase cleavage site and the well-studied Swedish mutation (KM670/671NL), which was predicted to be pathogenic . Molecular dynamics simulation indicated that the E674Q mutation resulted in a rearrangement of the interaction mode between APP and BACE1 and that the E674Q mutation was more prone to cleavage by BACE1. The results suggested that the E674Q mutation was pathogenic by facilitating the BACE1-mediated processing of APP and the production of Aβ. Furthermore, we applied an adeno-associated virus (AAV)-mediated transfer of the human E674Q mutant APP gene to the hippocampi of two-month-old C57Bl/6 J mice. AAV-E674Q-injected mice exhibited impaired learning behavior and increased pathological burden in the brain, implying that the E674Q mutation had a pathogenicity that bore a comparison with the classical Swedish mutation. Collectively, we report a strong amyloidogenic effect of the E674Q substitution in AD. To our knowledge, E674Q is the only pathogenic mutation within the amyloid processing sequence causing LOAD.