HEME OXYGENASE-l AND ALZHEIMER DISEASE

Alzheimer disease (AD) is a dementing illness characterized by progressive neuronal degeneration, gliosis, and the accumulation of intracellular inclusions (neurofibrillary tangles) and extracellular deposits of amyloid (senile plaques) in discrete regions of the basal forebrain, hippocampus, and association cortices (Selkoe, 1991). Sporadic AD is more common than all other aging-related neurodegenerative disorders combined, affecting approximately 5-10% of North Americans aged 65 and as many as 30--50% of those who survive to the end of their ninth decade (Katzman, 1993). Although the precise mechanisms responsible for neuronal demise in AD remain largely unknown, there exists ample evidence implicating oxidative stress (free radical injury) and mitochondrial insufficiency (ATP depletion) in the pathogenesis of this condition (Reichmann and Riederer, 1994; Beal, 1995; Mattson, 1997). These pathological features may, in turn, be related to the excessive sequestration of redox-active iron, an important generator of damaging reactive oxygen species (ROS), that has been documented in the basal forebrain and association cortices of AD victims (Schipper, 1998a; Sayre et aI., 2001). In both the AD and Parkinson brain, regional concentrations of transferrin binding sites remain unchanged or vary inversely with the elevated iron stores. These observations suggest that the transferrin pathway of