Real-time heterogeneity of supramolecular assembly of amyloid precursor protein is modulated by an endocytic risk factor PICALM
Abstract Recently, the localization of amyloid precursor protein (APP) into reversible nanoscale supramolecular assembly or “nanodomains” has been highlighted as crucial towards understanding the onset of the molecular pathology of Alzheimer’s disease (AD). Surface expression of APP is regulated by proteins interacting with it, controlling its retention and lateral trafficking on the synaptic membrane. Here, we evaluated the involvement of a key risk factor for AD, PICALM, as a critical regulator of nanoscale dynamics of APP. Although it was enriched in the postsynaptic density, PICALM was also localized to the presynaptic active zone and the endocytic zone. PICALM colocalized with APP and formed nanodomains with distinct morphological properties in different subsynaptic regions. Next, we evaluated if this localization to subsynaptic compartments was regulated by the C-terminal sequences of APP, namely, the “$ Y_{682} %$ ENPTY_{687} $” domain. Towards this, we found that deletion of C-terminal regions of APP with partial or complete deletion of $ Y_{682} %$ ENPTY_{687} $, namely, APP–Δ9 and APP–Δ14, affected the lateral diffusion and nanoscale segregation of APP. Lateral diffusion of APP mutant APP–Δ14 sequence mimicked that of a detrimental Swedish mutant of APP, namely, APP–SWE, while APP–Δ9 diffused similar to wild-type APP. Interestingly, elevated expression of PICALM differentially altered the lateral diffusion of the APP C-terminal deletion mutants. These observations confirm that the C-terminal sequence of APP regulates its lateral diffusion and the formation of reversible nanoscale domains. Thus, when combined with autosomal dominant mutations, it generates distinct molecular patterns leading to onset of Alzheimer’s disease (AD)..
| Medienart: |
E-Artikel |
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| Erscheinungsjahr: |
2023 |
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| Erschienen: |
2023 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:80 |
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| Enthalten in: |
Cellular and molecular life sciences - 80(2023), 10 vom: 20. Sept. |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Belapurkar, Vivek [VerfasserIn] |
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| Links: |
Volltext [lizenzpflichtig] |
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| Themen: |
Alzheimer’s disease |
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| Anmerkungen: |
© The Author(s), under exclusive licence to Springer Nature Switzerland AG 2023. Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law. |
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| doi: |
10.1007/s00018-023-04939-w |
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| funding: |
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| Förderinstitution / Projekttitel: |
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| 520 | |a Abstract Recently, the localization of amyloid precursor protein (APP) into reversible nanoscale supramolecular assembly or “nanodomains” has been highlighted as crucial towards understanding the onset of the molecular pathology of Alzheimer’s disease (AD). Surface expression of APP is regulated by proteins interacting with it, controlling its retention and lateral trafficking on the synaptic membrane. Here, we evaluated the involvement of a key risk factor for AD, PICALM, as a critical regulator of nanoscale dynamics of APP. Although it was enriched in the postsynaptic density, PICALM was also localized to the presynaptic active zone and the endocytic zone. PICALM colocalized with APP and formed nanodomains with distinct morphological properties in different subsynaptic regions. Next, we evaluated if this localization to subsynaptic compartments was regulated by the C-terminal sequences of APP, namely, the “$ Y_{682} %$ ENPTY_{687} $” domain. Towards this, we found that deletion of C-terminal regions of APP with partial or complete deletion of $ Y_{682} %$ ENPTY_{687} $, namely, APP–Δ9 and APP–Δ14, affected the lateral diffusion and nanoscale segregation of APP. Lateral diffusion of APP mutant APP–Δ14 sequence mimicked that of a detrimental Swedish mutant of APP, namely, APP–SWE, while APP–Δ9 diffused similar to wild-type APP. Interestingly, elevated expression of PICALM differentially altered the lateral diffusion of the APP C-terminal deletion mutants. These observations confirm that the C-terminal sequence of APP regulates its lateral diffusion and the formation of reversible nanoscale domains. Thus, when combined with autosomal dominant mutations, it generates distinct molecular patterns leading to onset of Alzheimer’s disease (AD). | ||
| 650 | 4 | |a Alzheimer’s disease |7 (dpeaa)DE-He213 | |
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| 650 | 4 | |a Lateral diffusion |7 (dpeaa)DE-He213 | |
| 650 | 4 | |a Nanodomains |7 (dpeaa)DE-He213 | |
| 650 | 4 | |a Super resolution microscopy |7 (dpeaa)DE-He213 | |
| 650 | 4 | |a Nanoscale organization |7 (dpeaa)DE-He213 | |
| 650 | 4 | |a Single particle tracking |7 (dpeaa)DE-He213 | |
| 650 | 4 | |a Amyloid precursor protein |7 (dpeaa)DE-He213 | |
| 650 | 4 | |a PICALM |7 (dpeaa)DE-He213 | |
| 650 | 4 | |a Synapses |7 (dpeaa)DE-He213 | |
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| 700 | 1 | |a Nair, Deepak |0 (orcid)0000-0002-2103-1653 |4 aut | |
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