Alzheimer’s disease is a widely recognised disorder caused by the progressive deterioration and death of brain cells. A key feature of the disease is the formation of structures called plaques in the brain. Plaques occur when many copies of a molecule known as amyloid beta stick together outside of the brain cells. Healthy brains also produce amyloid beta but it is in a different form, which cannot form plaques.

One in twenty people with Alzheimer’s disease have a family history of the disease. Of these, many are linked to changes in a gene that produces a protein called Presenilin 1 (or PS1 for short). Cells need PS1 to make amyloid beta and the altered versions of PS1 produce the type of amyloid beta that causes Alzheimer’s disease. Yet, in cases that do not run in families, the gene for PS1 is unchanged but the PS1 protein still produces the form of amyloid beta that is linked to Alzheimer’s disease.

Maesako, Horlacher et al. wanted to find out how seemingly healthy PS1 proteins can be made to produce plaque-forming amyloid betas. Studies of PS1 from mice revealed that small chemical modifications, called phosphate groups, could be attached to PS1 in a process called phosphorylation. Modified PS1 proteins produce harmful amyloid betas and removing the modifications was enough to make PS1 behave normally again. Maesako, Horlacher et al. found three points in the PS1 protein where phosphorylation could change the behaviour of the protein, the most important one is a site called Ser367.

Further investigation showed that an enzyme called Protein Kinase A (PKA) phosphorylates PS1; this enzyme is also able to attach phosphate groups to many different proteins. Maesako, Horlacher et al. went on to show that PS1 is phosphorylated in samples from people with Alzheimer’s disease, suggesting that this is a plausible cause for some cases of the disease. Finding a way to prevent phosphorylation or remove phosphate groups from PS1 could be the first step towards treating these cases of Alzheimer’s disease.

Senile plaques, comprised primarily of β-amyloid (Aβ), are the major pathological hallmark of Alzheimer’s disease (AD). Presenilin 1 (PS1) is the catalytic component of γ-secretase (Wolfe et al., 1999; Esler et al., 2000; Li et al., 2000), which is responsible for the final enzymatic cleavage of amyloid precursor protein (APP) to generate Aβ (De Strooper et al., 1998). Over 180 familial AD mutations have been identified in the PS1 gene, and the majority of them lead to an increase in the Aβ42/40 ratio (De Strooper, 2007). PS1 knock-in mice carrying familial AD mutations exhibit decreased Aβ40 and Aβ42 levels but increased Aβ42/40 ratio and accelerated Aβ deposition (Xia et al., 2015). This supports the idea that up-regulation of the Aβ42/40 ratio rather than the total amount of Aβ has a strong impact on Aβ deposition and AD pathogenesis.

Using Förster resonance energy transfer (FRET)-based imaging techniques we have previously shown that familial AD mutations in PS1 increase the proximity of PS1 N-terminus (NT) to C-terminus (CT) or to the large cytoplasmic loop domain, causing the so called ‘closed’ pathogenic PS1 conformation (Berezovska et al., 2005; Uemura et al., 2009). On the other hand, several nonsteroidal anti-inflammatory drugs and PS1/γ-secretase modulators, which are known to decrease the Aβ42/40 ratio (Weggen et al., 2001; Page et al., 2008), drive PS1 into the ‘open’ conformation (Lleó et al., 2004; Uemura et al., 2009; Ohki et al., 2011). These reports indicate that PS1 conformational changes are tightly linked to changes of the Aβ42/40 ratio, suggesting that modulation of the pathogenic ‘closed’ PS1 conformation is a potential target for AD treatment.

A number of studies highlight the reciprocal relationship between elevation in intracellular Ca²⁺ levels and Aβ pathology. Notably, Aβ deposition is observed in brain regions exhibiting a high basal rate of neuronal activity in humans (Sperling et al., 2009). The idea that Aβ causes Ca²⁺ elevation is supported by several studies (Kuchibhotla et al., 2008; Lopez et al., 2008; Busche et al., 2012; Higuchi et al., 2012). On the other hand, aberrant Ca²⁺ homeostasis affects Aβ production. For example, acute stimulation of the entorhinal cortex using an optogenetic approach increases the Aβ42 level specifically in the projection area of the perforant pathway (Yamamoto et al., 2015). KCl-induced depolarization causes sustained release of Aβ42 from AD mouse model synaptoneurosomes (Kim et al., 2010). KCl-triggered Ca²⁺ influx elevates intracellular Aβ42/40 ratio in primary neurons (Pierrot et al., 2004). We recently reported that increases in Ca²⁺ levels induce the PS1 pathogenic ‘closed’ conformation in primary neurons, followed by an increase in the Aβ42/40 ratio (Kuzuya et al., 2016). Furthermore, PS1 is found in the ‘closed’ conformation in sporadic AD brain, and this pathogenic PS1 conformational shift correlates with the proximity to deposited Aβ (Wahlster et al., 2013). In this report, we address the detailed molecular mechanisms of the Ca²⁺-driven pathogenic ‘closed’ conformation of the PS1/γ-secretase.

Phosphorylation, one of the crucial post-translational modifications, is a rapid and dynamic event in cells, and represents a common mechanism of regulating protein conformation and/or activity. In PS1, fifteen phosphorylation sites have been identified (Kirschenbaum et al., 2001; Lau et al., 2002; Fluhrer et al., 2004; Kuo et al., 2008; Ryu et al., 2010; Matz et al., 2015). Although the phosphorylation of some of these sites affects the stability of PS1/γ-secretase (Lau et al., 2002; Kuo et al., 2008; Ryu et al., 2010), the impact of phosphorylation on PS1 conformation and function has not yet been tested. Here, using FRET-based imaging we show that phosphorylation-inhibited mutations at the three domains (domain 1: T74, domain 2: S310, S313, and domain 3: S365, S366 and S367) prevents the Ca²⁺-mediated PS1 ‘closed’ conformational change. Conversely, phosphorylation-mimicking mutations reveal that domain 1 and 2 phosphorylation is necessary, but domain 3, and S367 in particular, is crucial for causing the PS1 pathogenic ‘closed’ conformation. Moreover, Protein Kinase A (PKA) inhibitors prevent the Ca²⁺-induced PS1 ‘closed’ conformational change whereas PKA activators trigger it. Therefore, we conclude that the Ca²⁺-increased PKA activity leads to phosphorylation of PS1 at the three domains, inducing the PS1 pathogenic ‘closed’ conformation. These results provide strong evidence that PS1 phosphorylation at certain residues can potentially be molecular targets for AD prevention.

Increasing evidence suggests interactions between Ca²⁺ overload and Aβ in the pathogenesis of AD. Although it has been suggested that aberrant Ca²⁺ homeostasis affects Aβ production, the effect of Ca²⁺ elevations on PS1/γ-secretase function is unknown. We have recently reported that increases in Ca²⁺ levels induce the pathogenic change in PS1 conformation and increase the Aβ42/40 ratio in cultured neurons (Kuzuya et al., 2016). Considering the rapid and dynamic nature of the conformational changes, it is unlikely that this change is achieved through mechanisms involving transcription or reassembly of PS1 into de novo γ-secretase complexes. However, the detailed molecular mechanism remains unclear, and whether similar Ca²⁺-mediated PS1 conformational changes occur in vivo is unknown. Our current study addresses these questions and demonstrates that Ca²⁺/PKA-mediated PS1 phosphorylation at domain 1 (T74), domain 2 (S310, S313) and domain 3 (S365, S366, S367) is responsible for the PS1/γ-secretase pathogenic conformational change in vitro and in vivo.

The high level of serines and threonines in the PS1 N-terminus and in the large hydrophilic loop region suggests that the enzymatic function of PS1 can be modulated by its ‘phosphorylated’ and ‘dephosphorylated’ states. It has been reported that PS1 phosphorylation at several residues enhances stability of the PS1 CT fragment that is necessary for γ-secretase activity (Lau et al., 2002; Kuo et al., 2008; Ryu et al., 2010). Recently, Matz and colleagues have identified eleven new phosphorylation sites in PS1 (Matz et al., 2015). They showed that phosphorylation-inhibited mutations of these sites affect neither activity of the PS1/γ-secretase nor Aβ production. Our current study revealed that six amino acids: T74, S310, S313, S365, S366 and S367, all, except for S310, within the newly-discovered PS1 phosphorylation sites, are critical for the Ca²⁺-triggered PS1 pathogenic, ‘closed’ conformation linked to increased Aβ42/40 ratio (Berezovska et al., 2005; Isoo et al., 2007; Uemura et al., 2010; Wahlster et al., 2013; Kuzuya et al., 2016). We found that the conformation of the phosphorylation-inhibited PS1 mutants at these residues is not different from that of the WT PS1. This is consistent with the findings of unaltered Aβ42/40 ratio in cells expressing PS1 phosphorylation-inhibited mutants (Matz et al., 2015). However, the conformation of the phosphorylation-inhibiting mutants and WT PS1 is very different in the Ca²⁺ influx-stimulated condition. This finding suggests that phosphorylation of PS1 at these residues as a result of the Ca²⁺ influx/PKA activation underlies its conformational change.

Our data show that introducing phosphorylation-inhibited mutations within all six residues prevents the Ca²⁺ influx/PKA activation-triggered PS1 conformational change. This indicates that phosphorylation of domain 1 (T74), domain 2 (S310-S313) and domain 3 (S365-S366-S367) is important for PS1 adopting the ‘closed’ conformation. On the other hand, the results using phosphorylation-mimicking mutants revealed that phosphorylation of domain 1 and domain 2, though necessary, is not sufficient for the structural change of PS1. Whereas domain 3, specifically S367, is critical for PS1 achieving the ‘closed’ conformation. These results beg the questions of how domain 3 is phosphorylated and whether phosphorylation of domain 1 and domain 2 is involved in the Ca²⁺-triggered PS1 pathogenic conformational change. Although the domain 1 and domain two phosphorylation-mimicking PS1 isoform (T74D/S310D/S313D G-PS1-R) shows the same conformation as WT G-PS1-R, PKA activators were able to induce the ‘closed’ conformation of this mutant. Therefore, we conclude that PKA is involved in phosphorylation of domain 3. We propose the following model: PKA first phosphorylates PS1 at domain 2, which leads to spatial rearrangements around domain 1, and allows its phosphorylation. This subsequently changes the local conformation around domain 3, enabling its phosphorylation by PKA. This final phosphorylation of S365-S366-S367, with S367 being most crucial, drives the pathogenic conformational alteration of the PS1/γ-secretase (Figure 6—figure supplement 1A). We propose that local spatial rearrangement around domain three is a key step for PKA-induced domain three phosphorylation, and phosphorylation of domain 1 and domain 2 is necessary for this to occur. This model is consistent with the finding that PKA is able to phosphorylate only S310 within domain 2 in recombinant PS1 hydrophilic loop (263–407) peptide in vitro (Fluhrer et al., 2004). We reason that lack of domain 1 in this recombinant PS1 fragment does not allow change in the local conformation around domain 3, explaining why S365-S366-S367 are not phosphorylated by PKA in this recombinant PS1. Moreover, a recent structural simulation study has demonstrated that 350–373 residues of PS1 containing domain 3, are subject to major movements (Somavarapu and Kepp, 2016). It is highly likely that naturally occurring domain 1 and domain 2 phosphorylation events may trigger these local spatial rearrangements around the 350–373 residues of PS1. We confirmed that domain 1 or domain 3 phosphorylation-inhibited mutant PS1 were still able to get phosphorylated by PKA at domain 2 (Figure 6—figure supplement 1B), suggesting that domain 2 is the first step of the phosphorylation. Consistently, except for domain 2, there are no known PKA substrate consensus sequences (Ubersax and Ferrell, 2007) around domain 1 or domain 3 of PS1 (Figure 6—figure supplement 1C).

PS1 conformational shifts are reflected by consistent changes in the FRET efficiency, detected by both the antibody-based FLIM assay of endogenous PS1 and by spectral FRET using the G-PS1-R reporter. Of note, all FRET-based assays only report relative changes in the proximity between the fluorophores, which does not necessarily translate into comparable changes in the distance between the protein epitopes (PS1 NT-CT and NT-loop, in this case). However, regardless of which assay we use, increased Ca²⁺/PKA activation reliably and reproducibly increased the proximity between donor and acceptor fluorophores tagging PS1 NT-CT or NT-loop domains. This strongly suggests that we observe conformational changes in the entire PS1 molecule rather than just a change in the orientation of the donor and acceptor fluorophores.

We have also established and validated novel in vivo PS1 conformation assay. Topical KCl application significantly increased intracellular Ca²⁺ (mean = ~649 nM, ranging from 166 nM to 2793 nM) in WT mice brains, a concentration of Ca²⁺ consistent with that observed in AD mouse models displaying Ca²⁺ overload in vivo (mean = ~499 nM, ranging from 162 nM to 1535 nM) (Kuchibhotla et al., 2008). We verified that Ca²⁺ influx induces the pathogenic ‘closed’ PS1 conformation in vivo via PS1 S365/S366/S367 phosphorylation. The cAMP-triggered PKA activation in mouse brain and consecutive conformational change of the wild type PS1 that we report confirms PKA-mediated PS1 phosphorylation at endogenous levels. More importantly, we show up-regulation of the domain 2 (S310) phosphorylation in AD brains, demonstrating that Ca²⁺-driven PS1 phosphorylation at certain residues may be important factors contributing to the pathogenesis of AD. Of note, a wide distribution of the phosphorylated PS1 levels observed in AD cases did not correlate with either age or PMI. Since we have selected a relatively homogenous group of AD brains in terms of pathology, Braak and CERAD scores could not be used to explain the wide distribution. Further investigation is necessary to determine if other factors, such as medications taken, disease duration, ApoE genotype, etc. could have affected the p-PS1 levels.

We propose a positive feed-forward mechanism for the pathogenesis of AD (Figure 6): once AD pathology, i.e. Aβ oligomers or deposited Aβ, triggers Ca²⁺ overload, domains 1, 2 and 3 of PS1 can be hyper-phosphorylated by PKA. This induces the pathogenic ‘closed’ PS1 conformation, and leads to subsequent elevation of the Aβ42/40 ratio, followed by accelerated Aβ oligomerization or deposition. In line with these findings, we have previously reported that PS1 shows a ‘closed’ conformation around Aβ plaques in the sporadic AD brain (Wahlster et al., 2013), and that higher Aβ42/40 ratio leads to the pathogenic conformation of PS1/γ-secretase (Zoltowska et al., 2016). It is conceivable that selective inhibition of PS1 phosphorylation at the domain 1, 2 and/or 3 may present a novel opportunity for therapeutics for AD. Since phosphorylation-inhibited PS1 mutations on these sites do not affect assembly, maturation, or activity of the PS1/γ-secretase (Matz et al., 2015), inhibition of these PS1 phosphorylation residues would affect neither the cleavage of Notch nor other γ-secretase substrates. On the other hand, inhibition of PKA activity may not be a suitable approach to prevent PS1 phosphorylation, due to multiple PKA substrates and potential off target effects in the brain and in the periphery. In future studies, PS1-targeting agents that selectively block PS1 phosphorylation at either one of the three residues could be identified, and their efficacy could be examined in vivo using our novel PS1 conformation assays.

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Author details

1. Masato Maesako

   Alzheimer’s Disease Research Laboratory, MassGeneral Institute for Neurodegenerative Disease, Massachusetts General Hospital, Harvard Medical School, Charlestown, United States

   Contribution

   MM, Acquisition of data; Analysis and interpretation of data; Drafting or revising the article

   Contributed equally with

   Jana Horlacher

   Competing interests

   The authors declare that no competing interests exist.

   "This ORCID iD identifies the author of this article:" 0000-0002-1970-2462

2. Jana Horlacher

   1. Alzheimer’s Disease Research Laboratory, MassGeneral Institute for Neurodegenerative Disease, Massachusetts General Hospital, Harvard Medical School, Charlestown, United States
   2. Department of Neurology, University of Ulm, Ulm, Germany

   Contribution

   JH, Acquisition of data, Analysis and interpretation of data

   Contributed equally with

   Masato Maesako

   Competing interests

   The authors declare that no competing interests exist.

3. Katarzyna M Zoltowska

   Alzheimer’s Disease Research Laboratory, MassGeneral Institute for Neurodegenerative Disease, Massachusetts General Hospital, Harvard Medical School, Charlestown, United States

   Contribution

   KMZ, Acquisition of data, Contributed unpublished essential data or reagents

   Competing interests

   The authors declare that no competing interests exist.

   "This ORCID iD identifies the author of this article:" 0000-0001-5853-3465

4. Ksenia V Kastanenka

   Alzheimer’s Disease Research Laboratory, MassGeneral Institute for Neurodegenerative Disease, Massachusetts General Hospital, Harvard Medical School, Charlestown, United States

   Contribution

   KVK, Acquisition of data, Contributed unpublished essential data or reagents

   Competing interests

   The authors declare that no competing interests exist.

5. Eleanna Kara

   Alzheimer’s Disease Research Laboratory, MassGeneral Institute for Neurodegenerative Disease, Massachusetts General Hospital, Harvard Medical School, Charlestown, United States

   Contribution

   EK, Acquisition of data, Analysis and interpretation of data

   Competing interests

   The authors declare that no competing interests exist.

6. Sarah Svirsky

   Alzheimer’s Disease Research Laboratory, MassGeneral Institute for Neurodegenerative Disease, Massachusetts General Hospital, Harvard Medical School, Charlestown, United States

   Contribution

   SS, Acquisition of data, Analysis and interpretation of data

   Competing interests

   The authors declare that no competing interests exist.

7. Laura J Keller

   Alzheimer’s Disease Research Laboratory, MassGeneral Institute for Neurodegenerative Disease, Massachusetts General Hospital, Harvard Medical School, Charlestown, United States

   Contribution

   LJK, Acquisition of data, Analysis and interpretation of data

   Competing interests

   The authors declare that no competing interests exist.

8. Xuejing Li

   Alzheimer’s Disease Research Laboratory, MassGeneral Institute for Neurodegenerative Disease, Massachusetts General Hospital, Harvard Medical School, Charlestown, United States

   Contribution

   XL, Conception and design, Analysis and interpretation of data

   Competing interests

   The authors declare that no competing interests exist.

9. Bradley T Hyman

   Alzheimer’s Disease Research Laboratory, MassGeneral Institute for Neurodegenerative Disease, Massachusetts General Hospital, Harvard Medical School, Charlestown, United States

   Contribution

   BTH, Conception and design, Analysis and interpretation of data

   Competing interests

   The authors declare that no competing interests exist.

10. Brian J Bacskai

    Alzheimer’s Disease Research Laboratory, MassGeneral Institute for Neurodegenerative Disease, Massachusetts General Hospital, Harvard Medical School, Charlestown, United States

    Contribution

    BJB, Conception and design, Analysis and interpretation of data, Drafting or revising the article

    Competing interests

    The authors declare that no competing interests exist.

11. Oksana Berezovska

    Alzheimer’s Disease Research Laboratory, MassGeneral Institute for Neurodegenerative Disease, Massachusetts General Hospital, Harvard Medical School, Charlestown, United States

    Contribution

    OB, Conception and design; Acquisition of data; Analysis and interpretation of data; Drafting or revising the article

    For correspondence

    OBEREZOVSKA@mgh.harvard.edu

    Competing interests

    The authors declare that no competing interests exist.

    "This ORCID iD identifies the author of this article:" 0000-0003-4898-5788

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