Several studies have documented the involvement of oxidative stress represented by lipid peroxidation in the pathogenesis of Alzheimer's disease (AD). To test whether the highly reactive carbonyl crotonaldehyde (CRA), generated during lipid peroxidation, is involved in AD, we performed an immunohistochemical analysis in AD and age-matched control hippocampi using a specific antibody against protein-bound CRA (P-CRA). In the AD cases, P-CRA immunoreactivity was preferentially localized in reactive astrocytes and microglia around senile plaques (SPs) and those present in the neuropil, while it was weakly detectable in neurons and neurofibrillary tangles. P-CRA immunoreactivity was also localized in all portions of diffuse SPs and the dystrophic neurites of neuritic and classical SPs, but was undetectable in amyloid cores. Age-matched controls showed P-CRA immunoreactivity only very weakly in neurons. In contrast to P-CRA, immunoreactivities for protein-bound acrolein and 4-hydroxy-2-nonenal were mainly localized to neurons and rarely seen in glial cells. Our results suggest that increased oxidative stress and CRA formation in glial cells is implicated in the disease processes of AD.