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.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
Heme is an essential cell metabolite, intracellular regulatory molecule, and protein prosthetic group. Given the known alterations in heme metabolism and redox metal distribution and the ...up-regulation of heme oxygenase enzyme in Alzheimer's disease (AD), we hypothesized that heme dyshomeostasis plays a key role in the pathogenesis. To begin testing this hypothesis, we used qRT-PCR to quantify the expression of aminolevulinate synthase (ALAS1) and porphobilinogen deaminase (PBGD), rate-limiting enzymes in the heme biosynthesis pathway. The relative expression of ALAS1 mRNA, the first and rate-limiting enzyme for heme biosynthesis under normal physiological conditions, was significantly (
p
<
0.05) reduced by nearly 90% in AD compared to control. Coordinately, the relative expression of PBGD mRNA, which encodes porphobilinogen deaminase, the third enzyme in the heme synthesis pathway and a secondary rate-limiting enzyme in heme biosynthesis, was also significantly (
p
<
0.02) reduced by nearly 60% in AD brain compared to control and significantly related to apolipoprotein E genotype (
p
<
0.005). In contrast, the relative expression of ALAD mRNA, which encodes aminolevulinate dehydratase, the second and a non-rate-limiting enzyme for heme biosynthesis, was unchanged between the two groups. Taken together, our results suggest regulation of cerebral heme biosynthesis is profoundly altered in AD and may contribute toward disease pathogenesis by affecting cell metabolism as well as iron homeostasis.
: The hemorrhagic strokes, intracerebral (ICH) and subarachnoid hemorrhage (SAH), often have poor outcomes. Indeed, the most common hemorrhagic stroke, ICH, has the highest mortality and morbidity ...rates of any stroke subtype. In this report, we discuss the evidence for the staging of red blood cell removal after ICH and the significance of control of this process. The protective effects of clinically relevant metalloporphyrin heme oxygenase inhibitors in experimental models of ICH and in superficial siderosis are also discussed. We also examine literature paradoxes related to both heme and heme oxygenase in various disorders of the central nervous system. Last, new data are presented that support the concept that heme, although primarily a pro‐oxidant, can also have antioxidant properties.
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.
A hypothesis is proposed that reconciles the epidemiological observation of elevated homocysteine in Alzheimer's disease (AD) with clinical features of the disease, particularly evidence of increased ...oxidative stress. We propose homocysteine is involved in an iron dysregulation/oxidative stress cycle that has a central role in the pathogenesis of AD. The implications of the hypothesis and some strategies for testing it are discussed.
Summary This communication explores the temporal link between the age-associated increase in body iron stores and the age-related incidence of Alzheimer’s disease (AD), the most prevalent cause of ...senile dementia. Body iron stores that increase with age could be pivotal to AD pathogenesis and progression. Increased stored iron is associated with common medical conditions such as diabetes and vascular disease that increase risk for development of AD. Increased stored iron could also promote oxidative stress/free radical damage in vulnerable neurons, a critical early change in AD. A ferrocentric model of AD described here forms the basis of a rational, easily testable experimental therapeutic approach for AD, which if successful, would be both widely applicable and inexpensive. Clinical studies have shown that calibrated phlebotomy is an effective way to reduce stored iron safely and predictably without causing anemia. We hypothesize that reducing stored iron by calibrated phlebotomy to avoid iron deficiency will improve cerebrovascular function, slow neurodegenerative change, and improve cognitive and behavioral functions in AD. The hypothesis is eminently testable as iron reduction therapy is useful for chronic diseases associated with iron excess such as nonalcoholic steatohepatitis (NASH), atherosclerosis, hereditary hemochromatosis and thalassemia. Testing this hypothesis could provide valuable insight into the causation of AD and suggest novel preventive and treatment strategies.
Heme-
a, is the heme prosthetic group of cytochrome
c oxidase (COX), the terminal complex of the mitochondrial electron transport chain. We measured heme-
a levels in postmortem brain tissue from ...nine patients diagnosed with dementia: Alzheimer's disease (AD) was the primary diagnosis in five, AD/diffuse Lewy body disease (DLBD) was diagnosed in two, DLBD was diagnosed in one, and DLBD (severe)/AD (mild) was diagnosed in one. Eight non-demented patients who died from non-neurological causes served as controls. When the primary diagnosis was AD (AD and AD/DLBD), levels of cerebral heme-
a were increased almost two-fold on a protein basis compared to controls (
p
<
0.001). Using perfused and non-perfused rats we showed that measured levels of cerebral heme-
a were unaffected by the presence of blood in brain tissue. In mice we showed that levels of cerebral heme-
a were unaffected by 24
h of storage at 4
°C prior to freezing. These animal studies suggest that increased levels of cerebral heme-
a in AD were not due to blood in postmortem brain or variation in postmortem interval.
Heme oxygenase, the rate-limiting step in heme catabolism, appears to play an important role in a number of neurodegenerative disorders, such as Alzheimer disease. Interestingly, the spatial ...distribution of heme oxygenase-1 expression in diseased brain is essentially identical to that of the pathological expression of tau, suggesting a key role for both in disease progression. Like heme oxygenase, the expression, phosphorylation, and aggregation of tau are regulated through signal cascades, including the extracellular signal-regulated kinases, whose activities are modulated by oxidative stress. Therefore, the expression of tau and heme oxygenase-1 in a coordinated manner likely plays a pivotal role in the cytoprotection of neuronal cells. This places heme oxygenase at the center of disease pathogenesis and offers a novel therapeutic approach targeted at either the causes or consequences of enzyme induction.
Elevated plasma homocysteine is an independent risk factor for the development of Alzheimer disease, however, the precise mechanisms underlying this are unclear. In this article, we expound on a ...novel hypothesis depicting the involvement of homocysteine in a vicious circle involving iron dysregulation and oxidative stress designated as the ferric cycle (Dwyer et al., 2004). Moreover, we suspect that the development of a critical heme deficiency in vulnerable neurons is an additional consequence of ferric cycle activity. Oxidative stress and heme deficiency are consistent with many pathological changes found in Alzheimer disease including mitochondrial abnormalities and impaired energy metabolism, cell cycle and cell signaling abnormalities, neuritic pathology, and other features of the disease involving alterations in iron homeostasis such as the abnormal expression of heme oxygenase-1 and iron response protein 2. Based on the ferric cycle concept, we have developed a model of Alzheimer disease development and progression, which offers an explanation for why sporadic Alzheimer disease is different than normal aging and why familial Alzheimer disease and sporadic Alzheimer disease could have different etiologies but a common end-stage.
Primary cultures of chick embryo hepatocytes have been used to study the mechanisms by which various drugs and other chemicals cause accumulation of porphyrin intermediates of the heme pathway. When ...these cultures are incubated with the heme precursor, 5-aminolevulinic acid (ALA), there is a major accumulation of protoporphyrin. However, in the presence of ALA, addition of insulin caused a striking increase in accumulation of uroporphyrin I and coproporphyrin III, whereas addition of glucagon mainly caused an increase in uroporphyrin I. Treatment with both insulin and glucagon resulted in additive increases in uroporphyrin, but not coproporphyrin. Antioxidants abolished the uroporphyrin I accumulation and increased coproporphyrin III. Insulin caused an increase in uptake of ALA and an increase in porphobilinogen accumulation, suggesting that the accumulation of uroporphyrin I is due to increased flux through the heme pathway. Apparently, this increased flux could particularly affect the utilization of the intermediate hydroxymethylbilane, which would result in accumulation of uroporphyrin I.
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