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Alteration in synaptic nanoscale organization dictates amyloidogenic processing in Alzheimer's disease

Kedia, S and Ramakrishna, P and Netrakanti, PR and Singh, N and Sisodia, SS and Jose, M and Kumar, S and Mahadevan, A and Ramanan, N and Nadkarni, S and Nair, D (2021) Alteration in synaptic nanoscale organization dictates amyloidogenic processing in Alzheimer's disease. In: iScience, 24 (1).

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Official URL: https://doi.org/10.1016/j.isci.2020.101924


Despite intuitive insights into differential proteolysis of amyloid precursor protein (APP), the stochasticity behind local product formation through amyloidogenic pathway at individual synapses remain unclear. Here, we show that the major components of amyloidogenic machinery namely, APP and secretases are discretely organized into nanodomains of high local concentration compared to their immediate environment in functional zones of the synapse. Additionally, with the aid of multiple models of Alzheimer's disease (AD), we confirm that this discrete nanoscale chemical map of amyloidogenic machinery is altered at excitatory synapses. Furthermore, we provide realistic models of amyloidogenic processing in unitary vesicles originating from the endocytic zone of excitatory synapses. Thus, we show how an alteration in the stochasticity of synaptic nanoscale organization contributes to the dynamic range of C-terminal fragments β (CTFβ) production, defining the heterogeneity of amyloidogenic processing at individual synapses, leading to long-term synaptic deficits as seen in AD.

Item Type: Journal Article
Publication: iScience
Publisher: Elsevier Inc.
Additional Information: The copyright for this article belongs to the author.
Department/Centre: Division of Biological Sciences > Centre for Neuroscience
Date Deposited: 04 Aug 2023 05:15
Last Modified: 04 Aug 2023 05:15
URI: https://eprints.iisc.ac.in/id/eprint/82712

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