A ROLE FOR 4-HYDROXYNONENAL, AN ALDEHYDIC PRODUCT OF LIPID-PEROXIDATION, IN DISRUPTION OF ION HOMEOSTASIS AND NEURONAL DEATH INDUCED BY AMYLOID BETA-PEPTIDE

Peroxidation of membrane lipids results in release of the aldehyde 4-h ydroxynonenal (HNE), which is known to conjugate to specific amino aci ds of proteins and may alter their function. Because accumulating data indicate that free radicals mediate injury and death of neurons in Al zheimer's disease (AD) and because amyloid beta-peptide (A beta) can p romote free radical production, we tested the hypothesis that HNE medi ates A beta 25-35-induced disruption of neuronal ion homeostasis and c ell death. A beta induced large increases in levels of free and protei n-bound HNE in cultured hippocampal cells. HNE was neurotoxic in a tim e- and concentration-dependent manner, and this toxicity was specific in that other aldehydic lipid peroxidation products were not neurotoxi c. HNE impaired Na+,K+-ATPase activity and induced an increase of neur onal intracellular free Ca2+ concentration. HNE increased neuronal vul nerability to glutamate toxicity, and HNE toxicity was partially atten uated by NMDA receptor antagonists, suggesting an excitotoxic componen t to HNE neurotoxicity. Glutathione, which was previously shown to pla y a key role in HNE metabolism in nonneuronal cells, attenuated the ne urotoxicities of both A beta and HNE. The antioxidant propyl gallate p rotected neurons against A beta toxicity but was less effective in pro tecting against HNE toxicity. Collectively, the data suggest that HNE mediates A beta-induced oxidative damage to neuronal membrane proteins , which, in turn, leads to disruption of ion homeostasis and cell dege neration.