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Issue 15, 2020
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Real-time nanoscale organization of amyloid precursor protein

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Abstract

Despite an intuitive understanding of the role of APP in health and disease, there exist few attempts to dissect its molecular localization at excitatory synapses. Though the biochemistry involved in the enzymatic processing of APP is well understood, there is a void in understanding the nonuniformity of the product formation in vivo. Here, we employed multiple paradigms of single molecules and ensemble based nanoscopic imaging to reveal that APP molecules are organized into regulatory nanodomains that are differentially compartmentalized in the functional zones of an excitatory synapse. Furthermore, with the aid of high density single particle tracking, we show that the lateral diffusion of APP in live cells dictates an equilibrium between these nanodomains and their nano-environment, which is affected in a detrimental variant of APP. Additionally, we incorporate this spatio-temporal detail ‘in silico’ to generate a realistic nanoscale topography of APP in dendrites and synapses. This approach uncovers a nanoscale heterogeneity in the molecular organization of APP, depicting a locus for differential APP processing. This holistic paradigm, to decipher the real-time heterogeneity of the substrate molecules on the nanoscale, could enable us to better evaluate the molecular constraints overcoming the ensemble approaches used traditionally to understand the kinetics of product formation.

Graphical abstract: Real-time nanoscale organization of amyloid precursor protein

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Supplementary files

Article information


Submitted
03 Jan 2020
Accepted
13 Mar 2020
First published
19 Mar 2020

Nanoscale, 2020,12, 8200-8215
Article type
Communication

Real-time nanoscale organization of amyloid precursor protein

S. Kedia, P. Ramakrishna, P. R. Netrakanti, M. Jose, J. Sibarita, S. Nadkarni and D. Nair, Nanoscale, 2020, 12, 8200
DOI: 10.1039/D0NR00052C

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