Increased Iron and Free Radical Generation in Preclinical Alzheimer Disease and Mild Cognitive Impairment

Issue title: Similarities and Differences Between Mild Cognitive Impairment and Alzheimer's Disease

Guest editors: Mark A. Lovell

Article type: Research Article

Authors: Smith, Mark A.^{a; *} | Zhu, Xiongwei^a | Tabaton, Massimo^b | Liu, Gang^c | McKeel Jr., Daniel W.^d | Cohen, Mark L.^a | Wang, Xinglong^a | Siedlak, Sandra L.^a | Dwyer, Barney E.^{i; j} | Hayashi, Takaaki^e | Nakamura, Masao^f | Nunomura, Akihiko^g | Perry, George^{a; h}

Affiliations: [a] Department of Pathology, Case Western Reserve University, Cleveland, OH, USA | [b] Department of Neuroscience, Ophthalmology, and Genetics, University of Genoa, Genoa, Italy | [c] Department of Radiology, University of Utah, Salt Lake City, UT, USA | [d] Departments of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO, USA | [e] Hokkaido Institute of Public Health, Kita 19, Nishi 12, Kita-ku, Sapporo, Japan | [f] Department of Chemistry, Asahikawa Medical College, Asahikawa, Japan | [g] Department of Neuropsychiatry, Interdisciplinary Graduate School of Medicine and Engineering, University of Yamanashi, Chuo, Yamanashi, Japan | [h] UTSA Neurosciences Institute and Department of Biology, College of Sciences, University of Texas at San Antonio, San Antonio, TX, USA | [i] Research Service, VA Medical Center, White River Junction, VT, USA | [j] Department of Neurology, Dartmouth Medical School, Hanover, NH, USA | Sanders-Brown Center on Aging and Alzheimer's Disease Center, Department of Chemistry, University of Kentucky, Lexington, Kentucky, USA

Correspondence: [*] Corresponding author: Mark A. Smith, Ph.D., Department of Pathology, Case Western Reserve University, 2103 Cornell Road, Cleveland, Ohio 44106, USA. Tel.: +1 216 368 3670; Fax: +1 216 368 8964; E-mail: [email protected].

Note: [] Handling Editor: Jesus Avila

Abstract: 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.

Keywords: Alzheimer's disease, chelator, diagnostic, free radicals, iron, mild cognitive impairment (MCI), oxidative stress, pre-clinical, redox activity

DOI: 10.3233/JAD-2010-1239

Journal: Journal of Alzheimer's Disease, vol. 19, no. 1, pp. 363-372, 2010