Real-time nanoscale organization of amyloid precursor protein

Kedia, S and Ramakrishna, P and Netrakanti, PR and Jose, M and Sibarita, J.B and Nadkarni, S and Nair, D (2020) Real-time nanoscale organization of amyloid precursor protein. In: Nanoscale, 12 (15). pp. 8200-8215.

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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. © 2020 The Royal Society of Chemistry.

Item Type:	Journal Article
Publication:	Nanoscale
Publisher:	Royal Society of Chemistry
Additional Information:	Copyright of this article belongs to Royal Society of Chemistry
Keywords:	Molecules; Topography, Amyloid precursor proteins; Intuitive understanding; Molecular localization; Molecular organization; Nano-scale heterogeneities; Nano-scale organization; Nanoscale topography; Single particle tracking, Nanotechnology
Department/Centre:	Division of Biological Sciences > Centre for Neuroscience
Date Deposited:	09 Apr 2021 09:05
Last Modified:	09 Apr 2021 09:05
URI:	http://eprints.iisc.ac.in/id/eprint/65282

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