In previous collaborative studies with Sayre and Perry, we detected immunoreactivity in brain tissue from an individual with Alzheimer's disease (AD).  The antibodies had been raised against pentylpyrrole derivatives that are produced by the reaction of 4-hydroxynon-2-enal (HNE) with protein.  No staining of similar tissue sections of nonAD brain was observed.  Especially interesting was the observation that not all of the neuronal cells stained contained the neurofibrillary tangles (NFT) that are a characteristic pathology of AD.  Thus, even cells that exhibit no other pathological changes (no NFT) contain oxidatively modified protein suggesting that an oxidative injury, not present in nonAD brain, is an early event in the disease process that preceeds the deposition of neurofibrillary tangles.

DHA-derived Oxidative Protein Modifications in Neurons

Lipids containing docosahexaenoic acid (DHA) are especially abundant in neuronal cells.  In view of the cytotoxicity reported for many lipid oxidation products, and the apparent relationship between AD and lipid-derived oxidative modifications of neuronal protein, we are investigating the involvement of DHA-derived oxidized lipids in neurodegenerative diseases.  In contrast with the oxidative cleavage of lipids containing arachidonate and linoleate esters that produces HNE, oxidative cleavage of DHA-containing lipids produces 4-hydroxyhex-2-enal (HHE).  Reaction of HHE with proteins produces ethylpyrrole derivatives rather than the pentylpyrroles generated in the reaction of HNE with proteins.  To provide a tool that can distinguish HNE from HHE-derived protein modifications, we are raising antibodies against protein ethylpyrrole derivatives. 

• Group Contacts: Bogdan Gugiu, Xiarong Gu
• Collaborator: G. Perry