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Updated: Jul 16, 2026
Modeling Neuronal Death and Degeneration in Mouse Primary Cerebellar Granule Neurons
Published on: November 6, 2017
PKC delta and NADPH oxidase in AGE-induced neuronal death
Mariapaola Nitti1, Anna L Furfaro, Nicola Traverso
1Department of Experimental Medicine, General Pathology Section, University of Genoa, Via L.B. Alberti 2, 16132 Genoa, Italy. paonit@medicina.unige.it
Abstract:
Advanced glycation end product (AGE) accumulation in brain is believed to contribute to neuronal death in several neurodegenerative diseases. Neurons exposed to AGEs undergo oxidative stress, but the molecular mechanisms able to induce ROS generation and cell death are not yet clear. In this work, we exposed SH-SY5Y neuroblastoma cells to glycated albumin, as a model of AGE-modified protein, and we observed that cells differentiated by retinoic acid died after AGE exposure, through anion superoxide and peroxide generation, while undifferentiated cells resulted resistant. Retinoic acid induced marked increase in p47phox expression and in catalytic activity of PKC delta: the upregulation of a pathway involving NADPH oxidase and PKC delta is likely to be responsible for neuronal susceptibility to AGE. This hypothesis is confirmed by the fact that pre-treatments of differentiated cells with DPI, an inhibitor of NADPH oxidase, or with rottlerin, an inhibitor of PKC delta, were able to prevent AGE-induced neuronal death.
Insights
Advanced glycation end products (AGEs) cause neuronal death in neurodegenerative diseases. Retinoic acid-treated cells showed susceptibility to AGEs via NADPH oxidase and PKC delta activation, leading to oxidative stress and cell death.
Area of Science:
- Neuroscience
- Biochemistry
- Cell Biology
Background:
- Advanced glycation end product (AGE) accumulation in the brain is linked to neuronal death in neurodegenerative diseases.
- The precise molecular mechanisms driving reactive oxygen species (ROS) generation and subsequent cell death upon AGE exposure remain unclear.
Purpose of the Study:
- To investigate the molecular mechanisms underlying neuronal susceptibility to AGEs.
- To identify key pathways involved in AGE-induced oxidative stress and cell death in neuronal cells.
Main Methods:
- SH-SY5Y neuroblastoma cells were exposed to glycated albumin as a model of AGE-modified protein.
- Cells were differentiated with retinoic acid to assess changes in susceptibility.
- Key molecular players, including NADPH oxidase and Protein Kinase C delta (PKC delta), were analyzed.
Main Results:
- Differentiated SH-SY5Y cells exposed to AGEs exhibited cell death mediated by superoxide anion and peroxide generation.
- Undifferentiated cells showed resistance to AGE-induced toxicity.
- Retinoic acid treatment upregulated p47phox expression and increased PKC delta activity, indicating a role for the NADPH oxidase pathway.
- Inhibitors of NADPH oxidase (DPI) and PKC delta (rottlerin) prevented AGE-induced neuronal death in differentiated cells.
Conclusions:
- Neuronal susceptibility to AGEs is mediated by a pathway involving NADPH oxidase and PKC delta, particularly in differentiated neurons.
- This pathway leads to increased ROS generation and subsequent cell death.
- Targeting NADPH oxidase or PKC delta may offer therapeutic strategies for neurodegenerative diseases associated with AGE accumulation.
