9 1995 by Humana Press Inc. All rights of any nature whatsoever reserved. 1044-7393/95/2402-03--0227 $04.80 Ultrastructural Localization of Heme Oxygenase-1 to the Neurofibriilary Pathology of Alzheimer Disease M. A. SMITH, *'1 P. L. RICHEY, 1 R. K. KUTTY,a B. WIGGERT, 2 AND G. PERRY 1 1Institute of Pathology, Case Western Reserve University, Cleveland, OH; and 2National Eye Institute, National Institutes of Health, Bethesda, MD Index Entries: Alzheimer disease; free radicals; aging; senile dementia; heine oxygenase-1; neurofibrillary pathology. INTRODUCTION Evidence for the important role of oxidation and free radicals in aging and Alzheimer disease (AD), the leading cause of senile dementia, is in- creasing (reviewed in Smith et al., 1994a). Indeed, we recently demon- strated that the antioxidant heme oxygenase-1 (HO-1) enzyme is localized to the neurofibrillary pathology of AD (Smith et al., 1994b). HO-1 is found intimately associated with the neurofibrillary tangles (NFT), senile plaque neurites, and neuropil threads within the Alzheimer brain, whereas con- trol brains show only sporadic lesion-related immunoreactivity in age- matched tissue and negligible background in tissue from young controls. HO-1 is an inducible microsomal enzyme that oxidatively cleaves heine, a pro-oxidant, to produce biliverdin and carbon monoxide. Bili- verdin is converted by biliverdin reductase to bilirubin, a potent antioxi- dant, whereas within the brain, carbon monoxide is suggested to act as a neurotransmitter. This latter aspect led to the suggestion that increased HO-1 activity might cause carbon monoxide-induced excitotoxicity and lead to neuronal degeneration (Smith et al., 1994b). The present article reports the electron microscopic localization of HO-1. *Author to whom all correspondence and reprint requests should be addressed. Molecular and Chemical Neuropathology 227 Vol. 24, 1995