Skip to main content
SpringerLink
Log in

Iron S Involvement in the Molecular Mechanisms and Pathogenesis of Alzheimers Disease

  • Chapter
Neuronal and Vascular Plasticity

Abstract

The subject of iron and iron regulation in the body has recently come under scrutiny as neurobiologists attempt to find underlying causes for neurodegenerative diseases such as Alzheimers, Parkinsons, and Huntington s and syndromes such as Hallervorden-Spatz. Each of these disorders includes iron accumulation in affected regions of the brain as a part of their pathogenic profile. Although it has long been known that iron is essential for life, what is not clear is how iron levels are maintained in a healthy nervous system and how these levels can become altered in disease states. The chapter will begin by addressing the normal role of iron in the body, because attempts for therapeutic intervention may begin at the level of iron absorption in the gut. In addition, understanding iron absorption by the gut may help to elucidate the mechanism by which iron is transported across the blood-brain-barrier (BBB). The remainder of the chapter will focus on the proposed role iron may play in Alzheimer s disease (AD) pathogenesis. The chapter will conclude with theories as to how known pathological mechanisms involved in AD may be controlled or at least influenced by a loss of iron regulation in the brain.

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Log in via an institution
Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 129.00
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 169.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD 169.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

References

  • Andrews, N (1999a). The Iron Transporter DMT1. The International Journal of Biochemistry and Cell Biology. 31(10): 991–994.

    Article  CAS  Google Scholar 

  • Andrews, N (1999b). Medical Progress: Disorders of Iron Metabolism. NEJM. 341(26): 1986–1995.

    Article  PubMed  CAS  Google Scholar 

  • Bartzokis, G, M Beckson, DB Hance, P Marx, JA Foster, and SR Marder. (1997). MR Evaluation of Age-Related Increase of Brain Iron in Young Adult and Older Normal Males. Magnetic Resonance Imaging. 15(1):29–35.

    Article  PubMed  CAS  Google Scholar 

  • Bisaglia, M, V Venezia, P Piccioli, S Stanzione, C Porcile, C Russo, F Mancini, C Milanese, and G Schettini. (2002). Acetaminophen Protects Hippocampal Neurons and PC12 Cultures from Amyloid Beta-Peptides Induced Oxidative Stress and Reduces NF-kappaB Activation. Neurochemistry International. 41: 43–54.

    Article  PubMed  CAS  Google Scholar 

  • Bruce, A, S Bose, W Fu, CM Butt, M-E Mirault, N Taniguchi, and MP Mattson. (1997). Amyloid Beta-Peptide Alters the Profile of Antioxidant Enzymes in Hippocampal Cultures in a Manner Similar to that Observed in Alzheimer’s Disease. Pathogenesis. 1: 15–30.

    CAS  Google Scholar 

  • Burdo, J, SL Menzies, IA Simpson, LM Garrick, MD Garrick, KG Dolan, DJ Haile, JL Beard, and JR Connor. (2001). Distribution of Divalent Metal Transporter 1 and Metal Transport Protein 1 in the Normal and Belgrade Rat. Journal of Neuroscience Research. 66(6): 1198–207.

    Article  PubMed  CAS  Google Scholar 

  • Burdo, JR and JR Connor. (2002). Iron Transport in the Central Nervous System. Molecular and Cellular Iron Transport. D. M. Templeton. New York, Marcel Dekker, Inc.

    Google Scholar 

  • Connor, J, EA Milward, S Moalem, M Sampietro, P Boyer, ME Percy, C Vergani, RJ Scott, and M Chorney. (2001). Is Hemochromatosis a Risk Factor for Alzheimer’s Disease? Journal of Alzheimer’s Disease. 3: 471–477.

    PubMed  CAS  Google Scholar 

  • Connor, JR (1997). Metals and Oxidative Damge in Neurological Disorders. New York, Plenum Press.

    Google Scholar 

  • Curtis, A, C Fey, CM Morris, LA Bindoff, PG Ince, PF Chinnery, A Coulthard, MJ Jackson, AP Jackson, DP McHale, D Hay, WA Barker, AF Markham, D Bates, A Curtis, and J Burn. (2001). Mutation in the Gene Encoding Ferritin Light Polypeptide Causes Dominant Adult-Onset Basal Ganglia Disease. Nature Genetics. 28: 350–354.

    Article  PubMed  CAS  Google Scholar 

  • Czech, C, G Tremp, and L Pradier. (2000). Presenilins and Alzheimer’s Disease: Biological Functions and Pathogenic Mechanisms. 60: 363–384.

    CAS  Google Scholar 

  • Deng, G, CJ Pike, and CW Cotman. (1996). Alzheimer-associated Presenilin-2 Confers Increased Sensitivity to Apoptosis in PC12 Cells. FEBS Letters. 397: 50–54.

    Article  PubMed  CAS  Google Scholar 

  • Earley CJ, RA, JL Beard, and JR Connor. (2000). Insight into the Pathophysiology of Restless Leg Syndrome. Journal of Neuroscience Research. 62(5): 623–628.

    Article  PubMed  CAS  Google Scholar 

  • Eisenstein, R (2000). Iron Regulatory Proteins and the Molecular Control of Mammalian Iron Metabolism. Annual Reviews — Nutrition. 20: 627–662.

    Article  CAS  Google Scholar 

  • Esler, W, and MS Wolfe. (2001). A Portrait of Alzheimer Secretases — New Features and Familiar Faces. Science. 293: 1449–1454.

    Article  PubMed  CAS  Google Scholar 

  • Esler, W, WT Kimberly, BS Ostaszewski, W Ye, TS Diehl, DJ Selkoe, and MS Wolfe. (2002). Activity-Dependent Isolation of the Presenilin-Gamma-Secretase Complex Reveals Nicastrin and a Gamma Substrate. PNAS. 99(5): 2720–2725.

    Article  PubMed  CAS  Google Scholar 

  • Gandy, S, J Naslund, and C Nordstedt. (2001). Molecular Consequences of Presenilin-l Mutation. Nature. 411: 654–655.

    Article  PubMed  CAS  Google Scholar 

  • Hallgren B and P Sourander. (1958). The Effect of Age on the Non-Haemin Iron in the Human Brain. Journal of Neurochemistry. 3: 41–51.

    Article  PubMed  CAS  Google Scholar 

  • Herreman, A, L Serneels, W Annaert, D Collen, L Schoonjans, and B DeStrooper. (2000). Total Inactivity of Gamma-Secretase Activity in Presenilin-Deficient Embryonic Stem Cells. Nature Cell Biology. 2: 461–462.

    Article  PubMed  CAS  Google Scholar 

  • Huang, X, MP Cuajungco, CS Atwood, RD Moir, RE Tanzi, and AI Bush. (2000). Alzheimer’s Disease, Beta-Amyloid Protein and Zinc. Journal of Nutrition. 130: 1488S–1429S.

    PubMed  CAS  Google Scholar 

  • Hulet, S, EJ Hess, W Debinski, P Arosio, K Bruce, S Powers, and JR Connor. (1999). Characterization and Distribution of Ferritin Binding Sites in the Adult and Mouse Brain. Journal of Neurochemistry. 72: 868–874.

    Article  PubMed  CAS  Google Scholar 

  • Hussain, R, CG Ballard, JA Edwardson, CM Morris. (2002). Transferrin Gene Polymorphism in Alzheimer’s Disease and Dementia with Lewy Bodies in Humans. Neuroscience Letters. 317: 13–16.

    Article  PubMed  CAS  Google Scholar 

  • Jeong, S-J, H-S Kim, K-A Chang, D-H Geum, CH Park, J-H Seo, J-C Rah, JH Lee, SH Choi, SG Lee, K Kim, and Y-H Sub. (2000). Subcellular Localization of Presenilins During Mouse Preimplantation Development. FASEB. 14: 2171–2176.

    Article  CAS  Google Scholar 

  • Keller, J, Q Guo, FW Holtsberg, AJ Bruce-Keller, and MP Mattson. (1998). Increased Sensitivity to Mitochondrial Toxin-Induced Apoptosis in Neural Cells Expressing Mutant Presenilin-l is Linked to Perturbed Calcium Homeostasis and Enhanced Oxyradical Production. Journal of Neuroscience. 18(12): 4439–4450.

    PubMed  CAS  Google Scholar 

  • Kesavapany, S, K-F Lau, DM McLoughlin, J Brownlees, S Ackerley, PN Leigh, CE Shaw, and CCJ Miller. (2001). p35/cdk5 Binds and Phosphorylates Beta-catenin and Regulates Beta-catenin/Presenilin-1 Interaction. European Journal of Neuroscience. 13: 241–247.

    PubMed  CAS  Google Scholar 

  • Kim, G, A Lewen, J-C Copin, BD Watson, and PH Chan. (2001). The Cytosolic Antioxidant, Cooper/Zinc Superoxide Dismutase, Attenuates Blood-Brain Barrier Disruption and Oxidative Cellular Injury After Photothrombotic Cortical Ischemia in Mice. Neuroscience. 105(4): 1007–1018.

    Article  PubMed  CAS  Google Scholar 

  • Liebner, S, H Germardt, and H Wolburg. (2000). Differential Expression of Endothelial Beta-catenin and Plakoglobin During Development and Maturation of the Blood-Brain and Blood-Retina Barrier in the Chicken. Developmental Dynamics. 217: 86–98.

    Article  PubMed  CAS  Google Scholar 

  • Lim, G, T Chu, F Yang, W Beech, SA Frautschy, and GM Cole. (2001). The Curry Spice Curcumin Reduces Oxidative Damage and Amyloid Pathology in an Alzheimer Transgenic Mouse. Journal of Neuroscience. 21(21): 8370–8377.

    PubMed  CAS  Google Scholar 

  • Loeffler, D, JR Connor, PL Juneau, BS Snyder, L Kanaley, AJ DeMaggio, H Nguyen, CM Brickman, and PA LeWitt. (1995). Transferrin and Iron in Normal, Alzheimer’s Disease, and Parkinson’s Disease Brain Regions. Journal of Neurochemistry. 65: 710–716.

    Article  PubMed  CAS  Google Scholar 

  • Lucas, J, F Hernandez, P Gomez-Ramos, MA Moran, R Hen, and J Avila. (2001). Decreased Nuclear Beta-catenin, Tau Hyperphosphorylation, and Neurodegeneration in GSK-3beta Conditional Trasgenic Mice. The EMBO Journal. 20(1&2): 27–39.

    Article  PubMed  CAS  Google Scholar 

  • Martin, W, Y Fq, and PS Allen. (1998). Increasing Striatal Iron Content Associated with Normal Aging. Movement Disorders. 13(2):281–286.

    Article  PubMed  CAS  Google Scholar 

  • Mattson, M, H Zhu, J Yu, and MS Kindy. (2000). Presenilin-1 Mutation Increases Neuronal Vulnerability to Focal Ischemia In Vivo and to Hypoxia and Glucose Deprivation in Cell Culture: Involvement of Perturbed Calcium Homeostasis. Journal of Neuroscience. 20(4): 1358–1364.

    PubMed  CAS  Google Scholar 

  • Mattson, M, WA Pedersen, W Duan, C Culmsee, and S Camandola. (1999). Cellular and Molecular Mechanisms Underlying Perturbed Energy Metabolism and Neuronal Degeneration in Alzheimer’s and Parkinson’ s Disease. Annals New York Academy of Sciences. 893: 154–175.

    Article  CAS  Google Scholar 

  • Mertsch, K, I Blasig, and T Grune. (2001). 4-Hydroxynonenal Impairs the Permeability of an in vitro Rat Blood-Brain Barrier. Neuroscience Letters. 314: 135–138.

    Article  PubMed  CAS  Google Scholar 

  • Michaud, M, G Lavigne, A Desautels, G Poirier, and J Montplaisir. (2002). Effects of Immobility on Sensory and Motor Symptoms of Restless Leg Syndrome. Movement Disorders. 17(1): 112–115.

    Article  PubMed  Google Scholar 

  • Moalem, S, ME Percy, DF Andrews, TPA Kruck, S Wong, AJ Dalton, P Mehta, B Fedor, and AC Warren. (2000). Are Hereditary Hemochromatosis Mutations Involved in Alzheimer’s Disease? American Journal of Medical Genetics. 93:58–66.

    Article  PubMed  CAS  Google Scholar 

  • Morris, C, JM Candy, AB Keith, AE Oakley, GA Taylor, RGL Pullen, CA Bloxham, A Gocht, and JA Edwardson. (1992). Brain Iron Homeostasis. Journal of Inorganic Biochemistry. 47: 257–265.

    Article  PubMed  CAS  Google Scholar 

  • Namekata, K, M Imagawa, A Terashi, S Ohta, F Oyama, Y Ihara. (1997). Association of Transferrin C2 Allele with Late-Onset Alzheimer’s Disease. Human Genetics. 101: 126–129.

    Article  PubMed  CAS  Google Scholar 

  • Nathke, I (1999). The Adenomatous Polyposis Coli Protein. Molecular Pathology. 52(4): 169–173.

    Article  PubMed  CAS  Google Scholar 

  • Palacino, J, MP Murphy, O Murayama, K Iwasaki, M Funiwara, A Takashima, TE Golde, and B Wolozin. (2001). Presenilin-l Regulates Beta-catenin-mediated Transcription in a Glycogen Synthase Kinase-3beta-Independent Fashion. Journal of Biological Chemistry. 276(42): 38563–38569.

    Article  PubMed  CAS  Google Scholar 

  • Parrish, A, JM Catania, J Orozco, and AJ Gandolfi. (1999). Chemically Induced Oxidative Stress Disrupts the E-cadherin/catenin Cell Adhesion Complex. Toxicology Science. 51(1): 80–86.

    Article  CAS  Google Scholar 

  • Piggott, M, EF Marshall, N Thomas, S Lloys, JA Court, E Jaros, D Burn, M Johnson, RH Perry, IG McKeith, C Ballard, and EK Perry. (1999). Striatal Dopaminergic Markers in Dementia with Lewy Bodies, Alzheimer’s, and Parkinson’s Diseases: Rostrocaudal Distribution. Brain. 122: 1449–1468.

    Article  PubMed  Google Scholar 

  • Pigino, G, A Pelsman, H Mori, and J Busciglio. (2001). Presenilin-1 Mutations Reduce Cytoskeletal Association, Deregulate Neurite Outgrowth, and Potentiate Neuronal Dystrophy and Tau Phosphorylation. Journal of Neuroscience. 21(3): 834–842.

    PubMed  CAS  Google Scholar 

  • Pinero, D, J Hu, and JR Connor. (2000). Alterations in the Interaction Between Iron and Regulatory Proteins and their Iron Responsive Element in Normal and Alzheimer’s Diseased Brains. Cellular and Molecular Biology. 46(4): 761–776.

    PubMed  CAS  Google Scholar 

  • Rafalowska, U, Gj Liu, RA Floyd. (1989). Peroxidation Induced Changes in Synaptosomal Transport of Dopamine and Gamma-Aminobutyric Acid. Free Radical Biology Medicine. 6: 485–492.

    Article  PubMed  CAS  Google Scholar 

  • Sampietro, M, L Caputo, A Casatta, M Meregalli, A Pellagatti, J Tagliabue, G Annoni, and C Vergani. (2001). The Hemochromatosis Gene Affects the Age of Onset of Sporadic Alzheimer’s Disease. Neurobiology of Aging. 22: 563–568.

    Article  PubMed  CAS  Google Scholar 

  • Schmelz, M, VJ Schmid, and AR Parrish. (2001). Selective Disruption of Cadherin/Catenin Complexes by Oxidative Stress in Precision-Cut Mouse Liver Slices. Toxicology Science. 61(2): 389–394.

    Article  CAS  Google Scholar 

  • Smith, M, PLR Harris, LM Sayre, and G Perry. (1997). Iron Accumulation in Alzheimer Disease is a Source of Redox-Generated Free Radicals. PNAS 94: 9866–9868.

    Article  PubMed  CAS  Google Scholar 

  • Soriano, S, DE Kang, M Fu, R Pestell, N Chevallier, H Zheng, and EH Koo. (2001). Presenilin-1 Negatively Regulates Beta-catenin/T Cell Factor/Lymphoid Enhancer Factor-l Signaling Independently of Beta-Amyloid Precursor Protein and Notch Processing. Journal of Cell Biology. 152(4): 785–794.

    Article  PubMed  CAS  Google Scholar 

  • Takashima, A, M Murayama, O Murayama, T Kohno, T Honda, K Yasutake, N Nihonmatsu, M Mercken, H Yamaguchi, S Sugihara, and B Wolozin. (1998). Presenilin-1 Associates with GSK 3-beta and its Substrate Tau. PNAS. 95: 9637–9641.

    Article  PubMed  CAS  Google Scholar 

  • Tan, E, SY Lum, and MC Wong. (2002). Restless Leg Syndrome in Parkinson’s Disease. Journal of Neurological Sciences. 196: 33–36.

    Article  CAS  Google Scholar 

  • Thinakaran, G (1999). The Role of Presenilins in Alzheimer’s Disease. Journal of Clinical Investigation. 104(10): 1321–1327.

    Article  PubMed  CAS  Google Scholar 

  • Thompson, K, S Shoham, and JR Connor. (2001). Iron and Neurodegenerative Disorders. Brain Research Bulletin. 55(2): 155–164.

    Article  PubMed  CAS  Google Scholar 

  • Tokuda, T, T Oide, A Tamaoka, K Ishii, S Matsuno, and S Ikeda. (2002). Prednisolone (30–60 mg/day) for Diseases Other than AD Decreases Amyloid Beta-Peptides in CSF. Neurology. 58: 1415–1418.

    Article  PubMed  CAS  Google Scholar 

  • Willis, A, GV Sawle, PR Guilbert, and ARJ Curtis. (2002). Palatal Tremor and Cognitive Decline in Neuroferritinopathy. Journal of Neurology, Neurosurgery, and Psychiatry. 73:86–95.

    Article  Google Scholar 

  • Zhang, Z, H Hartmann, VM Do, D Abramowski, C Sturchier-Pierrat, M Staufenbiel, B Sommer, M, van de Westering, H Clevers, P Saftig, B De Strooper, X He, and BA Yankner. (1998). Destablization of Beta-catenin by Mutations in Presenilin-1 Potentiates Neuronal Apoptosis. Nature. 395: 698–702.

    Article  PubMed  CAS  Google Scholar 

  • Zhu, H, Q Guo, MP Mattson. (1999). Dietary Restriction Protects Hippocampal Neurons Against the Death-Promoting Action of a Presenilin-l Mutation. Brain Res. 842: 224–229.

    Article  PubMed  CAS  Google Scholar 

  • Zubenko, G, J Farr, JS Stiffler, HB Hughes, BB Kaplan. (1992). Clinically-Silent Mutation in the Putative Iron-Responsive Element in Exon 17 of the Beta-Amyloid Precursor Protein Gene. Journal of Neuropathology and Experimental Neurology. 51(4): 459–463.

    Article  PubMed  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. George M. Leader Family Laboratory for Alzheimer s Disease Research, Pennsylvania State University College of Medicine, Hershey, PA, USA

    Rebecca J. Henderson & James R. Connor

  2. Department of Neuroscience and Anatomy, Pennsylvania State University College of Medicine, Hershey, PA, USA

    Rebecca J. Henderson & James R. Connor

  3. Department of Pharmacology, Pennsylvania State University College of Medicine, Hershey, PA, USA

    Rebecca J. Henderson & James R. Connor

Authors
  1. Rebecca J. Henderson
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. James R. Connor
    View author publications

    You can also search for this author in PubMed Google Scholar

Editor information

Editors and Affiliations

  1. Division of Cellular and Molecular Cerebral Ischemia Center for Molecular Medicine Institute for Environmental Health Sciences, Wayne State University School of Medicine, Detroit, MI, USA

    Kenneth Maiese (Professor of Neurology and Anatomy & Cell Biology Director) (Professor of Neurology and Anatomy & Cell Biology Director)

Rights and permissions

Reprints and permissions

Copyright information

© 2003 Springer Science+Business Media New York

About this chapter

Cite this chapter

Henderson, R.J., Connor, J.R. (2003). Iron S Involvement in the Molecular Mechanisms and Pathogenesis of Alzheimers Disease. In: Maiese, K. (eds) Neuronal and Vascular Plasticity. Springer, Boston, MA. https://doi.org/10.1007/978-1-4615-0282-1_7

Download citation

  • DOI: https://doi.org/10.1007/978-1-4615-0282-1_7

  • Publisher Name: Springer, Boston, MA

  • Print ISBN: 978-1-4613-5002-6

  • Online ISBN: 978-1-4615-0282-1

  • eBook Packages: Springer Book Archive

Publish with us

Policies and ethics

Search

Navigation