It is now established that oxidative stress is one of the earliest, if not the earliest, change that occurs in the pathogenesis of Alzheimer's disease (AD). Consistent with this, mild cognitive impairment (MCI), the clinical precursor of AD, is also characterized by elevations in oxidative stress. Since such stress does not operate in vacuo, in this study we sought to determine whether redox-active iron, a potent source of free radicals, was elevated in MCI and preclinical AD as compared to cognitively-intact age-matched control patients. Increased iron was found at the highest levels both in the cortex and cerebellum from the pre-clinical AD/MCI cases. Interestingly, glial accumulations of redox-active iron in the cerebellum were also evident in preclinical AD patients and tended to increase as patients became progressively cognitively impaired. Our findings suggests that an imbalance in iron homeostasis is a precursor to the neurodegenerative processes leading to AD and that iron imbalance is not necessarily unique to affected regions. In fact, an understanding of iron deposition in other regions of the brain may provide insights into neuroprotective strategies. Iron deposition at the preclinical stage of AD may be useful as a diagnostic tool, using iron imaging methods, as well as a potential therapeutic target, through metal ion chelators.

Increased expression of heme oxygenase-1 (HO-1) is a common feature in a number of neurodegenerative diseases. Interestingly, the spatial distribution of HO-1 expression in diseased brain is essentially identical to that of pathological expression of tau. In this study, we explored the relationship between HO-1 and tau, using neuroblastoma cells stably transfected with sense and antisense HO-1 constructs as well as with the vector alone. In transfected cells overexpressing HO-1, the activity of heme oxygenase was increased, and conversely, the level of tau protein was dramatically decreased when compared with antisense HO-1 or CEP transfected cells. The suppression of tau protein expression was almost completely reversed by zinc-deuteroporphyrin, a specific inhibitor of heme oxygenase activity. The activated forms of ERKs (extracellular signal-regulated kinases) were also decreased in cells overexpressing HO-1 although no changes in the expression of total ERK-1/2 proteins were observed. These data are in agreement with the finding that the expression of tau is regulated through signal cascades including the ERKs, whose activities are modulated by oxidative stresses. The expression of tau and HO-1 may be regulated by oxidative stresses in a coordinated manner and play a pivotal role in the cytoprotection of neuronal cells. Heme oxygenase (HO)1 is a microsomal enzyme that cleaves heme, a pro-oxidant, to produce biliverdin and carbon monoxide (1). Biliverdin is converted to a potent antioxidant (2), bilirubin, and carbon monoxide has been implicated to be a physiological regulator of cGMP and vascular tone (3, 4). The HO system is the rate-limiting step in heme degradation. To date, three HO isoforms (HO-1, HO-2, and HO-3) have been identified that catalyze this reaction. HO-1 is a 32-kDa heat shock protein (1, 5), which is inducible by numerous noxious stimuli (6, 7). HO-2 is a constitutively synthesized 36-kDa protein which is abundant in brain and testis (8). HO-3 is related to HO-2 but is the product of a different gene, and its ability to catalyze heme degradation is much less than that of HO-1 (9). Within the brain, the majority of HO activity is attributed to the HO-2 isozyme (8). The expression of HO-1 is normally very low in the brain but increases markedly after heat shock, ischemia, or glutathione depletion (8, 10 -12). In the normal rat brain, HO-1 is restricted to select neuronal and non-neuronal cell populations in the forebrain, diencephalon, cerebellum, and brainstem (10). However, after heat shock or ischemia, increased HO-1 is seen in neuronal and glial cells throughout the brain (10,(12)(13)(14).While the long-lived lesions of Alzheimer disease (AD) provide ample opportunity for oxidative modification because of their low rate of turnover (15), the more important issue is when, during the course of AD, oxidative abnormalities actually develop. Recent studies show that the oxidative damage associated with AD is represented by lipid peroxidation (16), nitration (17), reactive carbonyls (18), and n...

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