Abstract
The high levels of serine (S) and threonine (T) residues within the Presenilin 1 (PS1) N-terminus and in the large hydrophilic loop region suggest that the enzymatic function of PS1/γ-secretase can be modulated by its 'phosphorylated' and 'dephosphorylated' states. However, the functional outcome of PS1 phosphorylation and its significance for Alzheimer's disease (AD) pathogenesis is poorly understood. Here, comprehensive analysis using FRET-based imaging reveals that activity-driven and Protein Kinase A-mediated PS1 phosphorylation at three domains (domain 1: T74, domain 2: S310 and S313, domain 3: S365, S366, and S367), with S367 being critical, is responsible for the PS1 pathogenic 'closed' conformation, and resulting increase in the Aβ42/40 ratio. Moreover, we have established novel imaging assays for monitoring PS1 conformation in vivo, and report that PS1 phosphorylation induces the pathogenic conformational shift in the living mouse brain. These phosphorylation sites represent potential new targets for AD treatment.
Highlights
Senile plaques, comprised primarily of b-amyloid (Ab), are the major pathological hallmark of Alzheimer’s disease (AD)
Using the conformation sensitive Forster resonance energy transfer (FRET) probe, green fluorescent protein (GFP)-Presenilin 1 (PS1)-red fluorescent protein (RFP) (G-PS1-R) (Uemura et al, 2009), and the real-time FRET assay, we have previously shown that PS1 conformation is dynamically regulated by intracellular Ca2+
We show that treatment with KCl significantly increased the proximity between fluorescently labeled PS1 N-terminus (NT) and PS1 C-terminus (CT), indicating that KCl treatment triggers the ‘closed’ conformation of endogenous PS1
Summary
Senile plaques, comprised primarily of b-amyloid (Ab), are the major pathological hallmark of Alzheimer’s disease (AD). Several nonsteroidal anti-inflammatory drugs and PS1/g-secretase modulators, which are known to decrease the Ab42/40 ratio (Weggen et al, 2001; Page et al, 2008), drive PS1 into the ‘open’ conformation (Lleoet al., 2004; Uemura et al, 2009; Ohki et al, 2011). These reports indicate that PS1 conformational changes are tightly linked to changes of the Ab42/40 ratio, suggesting that modulation of the pathogenic ‘closed’ PS1 conformation is a potential target for AD treatment
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
