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Real-time heterogeneity of supramolecular assembly of amyloid precursor protein is modulated by an endocytic risk factor PICALM

Belapurkar, V. and Mahadeva Swamy, H.S. and Singh, N. and Kedia, S. and Setty, S.R.G. and Jose, M. and Nair, D. (2023) Real-time heterogeneity of supramolecular assembly of amyloid precursor protein is modulated by an endocytic risk factor PICALM. In: Cellular and Molecular Life Sciences, 80 (10).

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Official URL: https://doi.org/10.1007/s00018-023-04939-w


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 “Y682ENPTY687” domain. Towards this, we found that deletion of C-terminal regions of APP with partial or complete deletion of Y682ENPTY687, 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). © 2023, The Author(s), under exclusive licence to Springer Nature Switzerland AG.

Item Type: Journal Article
Publication: Cellular and Molecular Life Sciences
Publisher: Springer Science and Business Media Deutschland GmbH
Additional Information: The Copyright for this article belongs to the Springer Science and Business Media Deutschland GmbH.
Keywords: amyloid precursor protein; clathrin assembly protein; PICALM protein, human, Alzheimer disease; arthrogryposis; genetics; human; mutation; risk factor, Alzheimer Disease; Amyloid beta-Protein Precursor; Arthrogryposis; Humans; Monomeric Clathrin Assembly Proteins; Mutation; Risk Factors
Department/Centre: Division of Biological Sciences > Centre for Neuroscience
Division of Biological Sciences > Microbiology & Cell Biology
Date Deposited: 09 Nov 2023 10:43
Last Modified: 09 Nov 2023 10:43
URI: https://eprints.iisc.ac.in/id/eprint/83310

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