title: Increased iron and free radical generation in preclinical Alzheimer disease and mild cognitive impairment.
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.
authors.affiliation: Department of Pathology, Case Western Reserve University, Cleveland, OH 44106, USA. mark.smith@case.edu
authors.forename: Mark A
authors.initials: MA
authors.lastname: Smith
authors.forename: Xiongwei
authors.initials: X
authors.lastname: Zhu
authors.forename: Massimo
authors.initials: M
authors.lastname: Tabaton
authors.forename: Gang
authors.initials: G
authors.lastname: Liu
authors.forename: Daniel W
authors.initials: DW
authors.lastname: McKeel
authors.forename: Mark L
authors.initials: ML
authors.lastname: Cohen
authors.forename: Xinglong
authors.initials: X
authors.lastname: Wang
authors.forename: Sandra L
authors.initials: SL
authors.lastname: Siedlak
authors.forename: Barney E
authors.initials: BE
authors.lastname: Dwyer
authors.forename: Takaaki
authors.initials: T
authors.lastname: Hayashi
authors.forename: Masao
authors.initials: M
authors.lastname: Nakamura
authors.forename: Akihiko
authors.initials: A
authors.lastname: Nunomura
authors.forename: George
authors.initials: G
authors.lastname: Perry
mesh_terms: D000544:Alzheimer Disease / Q000378:metabolism* / Q000473:pathology; D000818:Animals; D001921:Brain / Q000378:metabolism / Q000473:pathology; D003072:Cognition Disorders / Q000378:metabolism* / Q000473:pathology; D005609:Free Radicals / Q000378:metabolism*; D006801:Humans; D007501:Iron / Q000378:metabolism*; D018384:Oxidative Stress / Q000502:physiology; D015854:Up-Regulation / Q000502:physiology*
chemical_list: D005609:Free Radicals; D007501:Iron