Several neurodegenerative conditions such as sporadic Creutzfeldt-Jakob disease (sCJD), Alzheimer's disease (AD), Parkinson's disease (PD), and Huntington's disease (HD) are associated with imbalance of iron homeostasis in diseased brains, raising the possibility that redox-iron induced oxidative damage plays a significant role in the neurotoxicity associated with these disorders. Recent evidence from the Singh laboratory indicates a significant reduction of ferroxidase activity in sCJD affected human and scrapie infected mouse brains. Combined with the fact that sCJD brains show a phenotype of 'apparent'iron deficiency despite the presence of normal or increased brain iron levels, these observations suggest dysregulation of the normal iron homeostatic machinery in diseased brains. A recent report demonstrates decreased ferroxidase activity leading to iron accumulation in AD brains, suggesting that this phenomenon is shared by neurodegenerative disorders of disparate etiology. In an independent set of studies, the Mukhopadhayay laboratory reported that ceruloplasmin (Cp), a major ferroxidase in the brain, is down regulated by reactive oxygen species (ROS). Since iron is highly redox-active and a major contributor of ROS if mismanaged, it is likely that once initiated by a specific disease process, iron imbalance is perpetuated by ROS through down regulation of major brain ferroxidases. Based on these observations, we hypothesize that ROS mediated misregulation of brain specific ferroxidases contributes to iron imbalance in AD and sCJD. The proposed studies will test this hypothesis in two specific aims.
In aim 1, the role of ROS in regulating specific ferroxidases will be investigated in cell models o AD and prion disease. Once the ferroxidases have been identified, their regulation will be compared with Cp which is known to be regulated by an mRNA decay mechanism in response to ROS. Subsequently, the minimal region of 3'UTR and binding proteins responsible for regulating ROS-mediated Cp activity will be identified.
In aim 2, the ferroxidases identified in ai 1 will be evaluated for their expression and activity in mouse models of AD and scrapie infection during disease progression. The results will be compared with human brain tissue from AD and sCJD cases using ferroxidase assay and immunohistochemistry as the read-out. Successful completion of these studies will clarify the role of major brain ferroxidases in iron dyshomeostasis associated with AD and sCJD brains, and provide the ground-work for future studies on the mechanism of brain iron dyshomeostasis in PD, HD, and other neurodegenerative conditions associated with brain iron imbalance.

Public Health Relevance

Accumulation of iron in diseased brains is a common feature of several neurodegenerative disorders including Alzheimer's disease (AD), Parkinson's disease, Huntington's disease, and sporadic Creutzfeldt-Jakob disease (sCJD). Since excess iron is redox-active, it is a significant cause of neurotoxicity in these disorders. Normally, brai iron metabolism is maintained by a group of proteins that regulate its uptake, release, and storage. Ceruplasmin (Cp) is a brain ferroxidase that regulates release of excess iron from cells. In this proposal we will investigate whether dysfunction of Cp or other brain ferroxidases causes accumulation of iron in diseased brains. These studies will clarify the cause of iron accumulation in AD and sCJD brains, and help in the development of therapeutic strategies aimed at restoring normal brain iron levels.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Exploratory/Developmental Grants (R21)
Project #
Application #
Study Section
Special Emphasis Panel (ZRG1-BDCN-L (52))
Program Officer
Wong, May
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Case Western Reserve University
Schools of Medicine
United States
Zip Code
Tripathi, Ajai K; Karmakar, Shilpita; Asthana, Abhishek et al. (2017) Transport of Non-Transferrin Bound Iron to the Brain: Implications for Alzheimer's Disease. J Alzheimers Dis 58:1109-1119
Baksi, Shounak; Tripathi, Ajai K; Singh, Neena (2016) Alpha-synuclein modulates retinal iron homeostasis by facilitating the uptake of transferrin-bound iron: Implications for visual manifestations of Parkinson's disease. Free Radic Biol Med 97:292-306
Tripathi, Ajai K; Singh, Neena (2016) Prion Protein-Hemin Interaction Upregulates Hemoglobin Synthesis: Implications for Cerebral Hemorrhage and Sporadic Creutzfeldt-Jakob Disease. J Alzheimers Dis 51:107-21
Haldar, Swati; Tripathi, Ajai; Qian, Juan et al. (2015) Prion protein promotes kidney iron uptake via its ferrireductase activity. J Biol Chem 290:5512-22
Tripathi, Ajai K; Haldar, Swati; Qian, Juan et al. (2015) Prion protein functions as a ferrireductase partner for ZIP14 and DMT1. Free Radic Biol Med 84:322-330
Singh, Neena; Asthana, Abhishek; Baksi, Shounak et al. (2015) The prion-ZIP connection: From cousins to partners in iron uptake. Prion 9:420-8
Singh, Neena (2014) The role of iron in prion disease and other neurodegenerative diseases. PLoS Pathog 10:e1004335
Singh, Ajay; Haldar, Swati; Horback, Katharine et al. (2013) Prion protein regulates iron transport by functioning as a ferrireductase. J Alzheimers Dis 35:541-52
Haldar, Swati; Beveridge, 'alim J; Wong, Joseph et al. (2013) A low-molecular-weight ferroxidase is increased in the CSF of sCJD cases: CSF ferroxidase and transferrin as diagnostic biomarkers for sCJD. Antioxid Redox Signal 19:1662-75
Singh, Ajay; Qing, Liuting; Kong, Qingzhong et al. (2012) Change in the characteristics of ferritin induces iron imbalance in prion disease affected brains. Neurobiol Dis 45:930-8

Showing the most recent 10 out of 11 publications