However, FAD– APP mutations result in high Aβ40/Aβ38 compared to wt APP.
APP mutations do not seem to impair the physiological functions of APP.
After 28 days of CoQ10 treatment, APP/PS1 or APP mutations have smaller infarct volumes, while the volumes of hemisphere and hippocampus on the infarcted side were larger than those treated with placebo.
All known APP mutations associated with CAA cluster within the Aβ-coding region of the gene (exons 16 and 17).
Here, we demonstrated that FAD-linked APP mutations do not directly alter calcium signaling when overexpressed in PC12 cells.
The Flemish and Arctic APP mutations increase the propensity for fibrillization and decrease proteolytic clearance of Aβ peptides [17], [18], [19], [20].
Thus, altered presentation of the APP substrate to γ-secretase, driven by either APP mutations or by binding of the pharmacological agents to APP could, in turn, allosterically affect PS1 conformation.
This could be reproduced in a transgenic mouse model [9] in which APP mutations led to increased incorporation of bromodeoxyuridine (BrdU) and enhanced expression of immature neuronal markers in two neuroproliferative regions: The subventricular zone and the dentate gyrus.
In line with this finding, we have previously showed that APP mutations which reduce Aβ42 lead to an "open" [15], whereas mutations that increase Aβ42 induce "close" [16] conformation of the PS1 molecule.
CRND8 mice carry two APP mutations (KM670/671NL 'Swedish' and V717F 'Indiana') and elevated levels of Aβ in hippocampus and through much of the neocortex from a young age [35].
APP mutations account for <0.1% of AD patients (13).
