Increased iron and free radical generation in preclinical Alzheimer disease and mild cognitive impairment

Department of Pathology, Case Western Reserve University, Cleveland, OH 44106, USA.
Journal of Alzheimer's disease: JAD (Impact Factor: 4.15). 01/2010; 19(1):363-72. DOI: 10.3233/JAD-2010-1239
Source: PubMed


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.

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    • "To cope with these two toxic damaging actions, living organisms have developed a tight regulation of iron metabolism to sustain proper concentration and organ distribution of this essential metal [2] [3]. Over that last decade, several groups have proposed that excess misregulated brain iron confers a toxicity that plays an important role in the pathogenesis of human neurodegenerative and metabolic diseases [4] [5] [6] [7] [8] [9] [10] [11]. "

    Full-text · Dataset · May 2015
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    • "We will take Aβ aggregation as a case study, where the interactions between Aβ42 and iron in vitro, and the relationship between Aβ and iron deposition in humans and AβPP mouse models, have been characterized by synchrotron methods (Collingwood et al., 2005a; Gallagher et al., 2012; Everett et al., 2014b). Many studies have demonstrated that iron is associated with insoluble deposits of Aβ in human brain, even in the pre-clinical stage of AD (Smith et al., 2010), and it is understood that iron provides much of the natural contrast that makes amyloid plaques observable in high resolution MRI (Meadowcroft et al., 2009; Petiet et al., 2011). However, observed accumulation of iron in amyloid plaques is reportedly lower in mouse models of AD than in human tissue (Leskovjan et al., 2009; Meadowcroft et al., 2009), and tissue iron concentration has been shown not to correlate with plaque burden in human AD cases (House et al., 2008). "
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    ABSTRACT: There is evidence for iron dysregulation in many forms of disease, including a broad spectrum of neurodegenerative disorders. In order to advance our understanding of the pathophysiological role of iron, it is helpful to be able to determine in detail the distribution of iron as it relates to metabolites, proteins, cells, and tissues, the chemical state and local environment of iron, and its relationship with other metal elements. Synchrotron light sources, providing primarily X-ray beams accompanied by access to longer wavelengths such as infra-red, are an outstanding tool for multi-modal non-destructive analysis of iron in these systems.The micro-and nano-focused X-ray beams that are generated at synchrotron facilities enable measurement of iron and other transition metal elements to be performed with outstanding analytic sensitivity and specificity. Recent developments have increased the scope for methods such as X-ray fluorescence mapping to be used quantitatively rather than semi-quantitatively. Burgeoning interest, coupled with technical advances and beamline development at synchrotron facilities, has led to substantial improvements in resources and methodologies in the field over the past decade. In this paper we will consider how the field has evolved with regard to the study of iron in proteins, cells, and brain tissue, and identify challenges in sample preparation and analysis. Selected examples will be used to illustrate the contribution, and future potential, of synchrotron X-ray analysis for the characterization of iron in model systems exhibiting iron dysregulation, and for human cases of neurodegenerative disorders including Alzheimer's disease, Parkinson's disease, Friedreich's ataxia, and amyotrophic lateral sclerosis.
    Full-text · Article · Aug 2014 · Frontiers in Pharmacology
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    • "Misregulation in brain iron has been considered to be one of the primary causes of neuronal death in neurodegenerative disorders (Qian et al., 1997; Qian and Shen, 2001; Lei et al., 2012). Evidence has also been gathered to imply that Aβ production, precipitation, and toxicity in AD are caused by abnormal interactions with neocortical iron (Zhu et al., 2004; Zhao et al., 2008; Smith et al., 2010). In a recent study (Huang et al., 2014), we demonstrated for the first time that HupA was able to reduce significantly the contents of insoluble and soluble A(β-40 and A(β-42 and hyperphosphorylated tau in the brain of APP/PS1 transgenic mice. "
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    ABSTRACT: Alzheimer's disease (AD) is a progressive neurodegenerative disorder for which there is no cure. Huperzine A (HupA) is a natural inhibitor of acetylcholinesterase (AChE) derived from the Chinese folk medicine Huperzia serrata (Qian Ceng Ta). It is a licensed anti-AD drug in China and is available as a nutraceutical in the US. A growing body of evidence has demonstrated that HupA has multifaceted pharmacological effects. In addition to the symptomatic, cognitive-enhancing effect via inhibition of AChE, a number of recent studies have reported that this drug has "non-cholinergic" effects on AD. Most important among these is the protective effect of HupA on neurons against amyloid beta-induced oxidative injury and mitochondrial dysfunction as well as via the up-regulation of nerve growth factor and antagonizing N-methyl-d-aspartate receptors. The most recent discovery that HupA may reduce brain iron accumulation lends further support to the argument that HupA could serve as a potential disease-modifying agent for AD and also other neurodegenerative disorders by significantly slowing down the course of neuronal death.
    Full-text · Article · Aug 2014 · Frontiers in Aging Neuroscience
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