Brain Ponderings podcast with Dr. Mark Mattson Allan Butterfield: Cell Membrane Lipid Peroxidation and Neuron Degeneration in Alzheimer's Disease
The outer membrane of cells is comprised of a lipid bilayer consisting of phospholipids, cholesterol, arachidonic acid, omega-3 fatty acids, and others. Embedded in the membrane are various proteins that play roles critical to the survival and function of the cell. Examples of membrane proteins of particular importance for neurons are: ion channels and ion 'pumps which control neuron excitability; glucose and ketone transporters which are critical for energy metabolism, and receptors for a myriad of neurotransmitters, neurotrophic factors, and other inter-cellular signaling molecules. In this episode chemistry Professor Allan Butterfield talks about research showing a pivotal role for free radicals generated by the Alzheimer's amyloid-peptide in triggering a chain reaction attack on membrane arachidonic acid resulting in the release of a toxic lipid fragment called 4-hydroxynonenal (HNE). HNE can bind irreversibly to certain amino acids on proteins (lysine, cysteine, histidine) thereby compromising the normal function of the protein. The Butterfield lab and my lab showed that binding of HNE to ion pump proteins, glucose transporters, and glutamate transporters renders neurons vulnerable to excitotoxicity in Alzheimer's disease. Interventions that suppress membrane lipid peroxidation or detoxify HNE may prevent or ameliorate Alzheimer's disease and other neurodegenerative disorders.
LINKS
Professor Butterfield's webpage:
https://chem.as.uky.edu/users/dabcns
Review articles
https://journals.physiology.org/doi/full/10.1152/physrev.00030.2022
https://pmc.ncbi.nlm.nih.gov/articles/PMC7502429/pdf/nihms-1583713.pdf
https://pmc.ncbi.nlm.nih.gov/articles/PMC7085980/pdf/nihms-1566301.pdf