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Reciprocal relationship between APP positioning relative to the membrane and PS1 conformation.

Uemura K, Farner KC, Nasser-Ghodsi N, Jones P, Berezovska O - Mol Neurodegener (2011)

Bottom Line: Several familial Alzheimer disease (FAD) mutations within the transmembrane region of the amyloid precursor protein (APP) increase the Aβ42/40 ratio without increasing total Aβ production.In the present study, we analyzed the impact of FAD mutations and γ-secretase modulators (GSMs) that alter the Aβ42/40 ratio on APP C-terminus (CT) positioning relative to the membrane, reasoning that changes in the alignment of the APP intramembranous domain and presenilin 1 (PS1) may impact the PS1/γ-secretase cleavage site on APP.Thus, we propose that there is a reciprocal relationship between APP-CT positioning relative to the membrane and PS1 conformation, suggesting that factors that modulate either APP positioning in the membrane or PS1 conformation could be exploited therapeutically.

View Article: PubMed Central - HTML - PubMed

Affiliation: Alzheimer Research Unit, MassGeneral Institute for Neurodegenerative Diseases, Massachusetts General Hospital, Charlestown, MA 02129, USA. oberezovska@partners.org.

ABSTRACT

Background: Several familial Alzheimer disease (FAD) mutations within the transmembrane region of the amyloid precursor protein (APP) increase the Aβ42/40 ratio without increasing total Aβ production. In the present study, we analyzed the impact of FAD mutations and γ-secretase modulators (GSMs) that alter the Aβ42/40 ratio on APP C-terminus (CT) positioning relative to the membrane, reasoning that changes in the alignment of the APP intramembranous domain and presenilin 1 (PS1) may impact the PS1/γ-secretase cleavage site on APP.

Results: By using a Förster resonance energy transfer (FRET)-based technique, fluorescent lifetime imaging microscopy (FLIM), we show that Aβ42/40 ratio-modulating factors which target either APP substrate or PS1/γ-secretase affect proximity of the APP-CT to the membrane and change PS1 conformation.

Conclusions: Thus, we propose that there is a reciprocal relationship between APP-CT positioning relative to the membrane and PS1 conformation, suggesting that factors that modulate either APP positioning in the membrane or PS1 conformation could be exploited therapeutically.

No MeSH data available.


Related in: MedlinePlus

A scheme of reciprocal interaction between APP-CT positioning relative to the membrane and PS1 conformation . Wild type PS1/γ-secretase can exist in an "open" and "close" conformational states that correlate with production of Aβ40 and Aβ42, respectively (Lleo, 2004, Berezovska 2005), with the "open" conformation being a predominant state (A). The C-terminus of APP bearing FAD mutation(s) associated with the increased Aβ42/40 ratio (orange/red) positions closer to the membrane (B), compared to that in the wild type APP (A). When incorporated into wild type PS1/γ-secretase, it can induce conformational change of PS1 by bringing PS1 NT and CT closer together [25]. On the other hand, when wild type APP is incorporated into FAD-mutant PS1/γ-secretase that predominantly exist in a "closed" conformation, the position of APP C-terminus changes and comes closer to the membrane (C).
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Figure 4: A scheme of reciprocal interaction between APP-CT positioning relative to the membrane and PS1 conformation . Wild type PS1/γ-secretase can exist in an "open" and "close" conformational states that correlate with production of Aβ40 and Aβ42, respectively (Lleo, 2004, Berezovska 2005), with the "open" conformation being a predominant state (A). The C-terminus of APP bearing FAD mutation(s) associated with the increased Aβ42/40 ratio (orange/red) positions closer to the membrane (B), compared to that in the wild type APP (A). When incorporated into wild type PS1/γ-secretase, it can induce conformational change of PS1 by bringing PS1 NT and CT closer together [25]. On the other hand, when wild type APP is incorporated into FAD-mutant PS1/γ-secretase that predominantly exist in a "closed" conformation, the position of APP C-terminus changes and comes closer to the membrane (C).

Mentions: In summary, our data demonstrate that interaction of the APP substrate with PS1/γ-secretase changes APP CT positioning relative to the membrane. Moreover, both APP-targeting and PS1-targeting manipulations that change the Aβ42/40 ratio can affect APP orientation relative to the membrane as well as PS1 conformation, indicating that APP-CT positioning and PS1 conformation are tightly interconnected, and are in a reciprocal relationship (Figure 4). Thus, exploring factors affecting PS1 as well as APP conformation would render more insights into the AD pathogenesis, and may provide new information about potential therapeutic targets.


Reciprocal relationship between APP positioning relative to the membrane and PS1 conformation.

Uemura K, Farner KC, Nasser-Ghodsi N, Jones P, Berezovska O - Mol Neurodegener (2011)

A scheme of reciprocal interaction between APP-CT positioning relative to the membrane and PS1 conformation . Wild type PS1/γ-secretase can exist in an "open" and "close" conformational states that correlate with production of Aβ40 and Aβ42, respectively (Lleo, 2004, Berezovska 2005), with the "open" conformation being a predominant state (A). The C-terminus of APP bearing FAD mutation(s) associated with the increased Aβ42/40 ratio (orange/red) positions closer to the membrane (B), compared to that in the wild type APP (A). When incorporated into wild type PS1/γ-secretase, it can induce conformational change of PS1 by bringing PS1 NT and CT closer together [25]. On the other hand, when wild type APP is incorporated into FAD-mutant PS1/γ-secretase that predominantly exist in a "closed" conformation, the position of APP C-terminus changes and comes closer to the membrane (C).
© Copyright Policy - open-access
Related In: Results  -  Collection

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Figure 4: A scheme of reciprocal interaction between APP-CT positioning relative to the membrane and PS1 conformation . Wild type PS1/γ-secretase can exist in an "open" and "close" conformational states that correlate with production of Aβ40 and Aβ42, respectively (Lleo, 2004, Berezovska 2005), with the "open" conformation being a predominant state (A). The C-terminus of APP bearing FAD mutation(s) associated with the increased Aβ42/40 ratio (orange/red) positions closer to the membrane (B), compared to that in the wild type APP (A). When incorporated into wild type PS1/γ-secretase, it can induce conformational change of PS1 by bringing PS1 NT and CT closer together [25]. On the other hand, when wild type APP is incorporated into FAD-mutant PS1/γ-secretase that predominantly exist in a "closed" conformation, the position of APP C-terminus changes and comes closer to the membrane (C).
Mentions: In summary, our data demonstrate that interaction of the APP substrate with PS1/γ-secretase changes APP CT positioning relative to the membrane. Moreover, both APP-targeting and PS1-targeting manipulations that change the Aβ42/40 ratio can affect APP orientation relative to the membrane as well as PS1 conformation, indicating that APP-CT positioning and PS1 conformation are tightly interconnected, and are in a reciprocal relationship (Figure 4). Thus, exploring factors affecting PS1 as well as APP conformation would render more insights into the AD pathogenesis, and may provide new information about potential therapeutic targets.

Bottom Line: Several familial Alzheimer disease (FAD) mutations within the transmembrane region of the amyloid precursor protein (APP) increase the Aβ42/40 ratio without increasing total Aβ production.In the present study, we analyzed the impact of FAD mutations and γ-secretase modulators (GSMs) that alter the Aβ42/40 ratio on APP C-terminus (CT) positioning relative to the membrane, reasoning that changes in the alignment of the APP intramembranous domain and presenilin 1 (PS1) may impact the PS1/γ-secretase cleavage site on APP.Thus, we propose that there is a reciprocal relationship between APP-CT positioning relative to the membrane and PS1 conformation, suggesting that factors that modulate either APP positioning in the membrane or PS1 conformation could be exploited therapeutically.

View Article: PubMed Central - HTML - PubMed

Affiliation: Alzheimer Research Unit, MassGeneral Institute for Neurodegenerative Diseases, Massachusetts General Hospital, Charlestown, MA 02129, USA. oberezovska@partners.org.

ABSTRACT

Background: Several familial Alzheimer disease (FAD) mutations within the transmembrane region of the amyloid precursor protein (APP) increase the Aβ42/40 ratio without increasing total Aβ production. In the present study, we analyzed the impact of FAD mutations and γ-secretase modulators (GSMs) that alter the Aβ42/40 ratio on APP C-terminus (CT) positioning relative to the membrane, reasoning that changes in the alignment of the APP intramembranous domain and presenilin 1 (PS1) may impact the PS1/γ-secretase cleavage site on APP.

Results: By using a Förster resonance energy transfer (FRET)-based technique, fluorescent lifetime imaging microscopy (FLIM), we show that Aβ42/40 ratio-modulating factors which target either APP substrate or PS1/γ-secretase affect proximity of the APP-CT to the membrane and change PS1 conformation.

Conclusions: Thus, we propose that there is a reciprocal relationship between APP-CT positioning relative to the membrane and PS1 conformation, suggesting that factors that modulate either APP positioning in the membrane or PS1 conformation could be exploited therapeutically.

No MeSH data available.


Related in: MedlinePlus