TITLE: Commentary:
Is Alzheimer's disease iron overload of the brain?
(the full text paper is unavailable)
JOURNAL: Alzheimer's Research
VOLUME: 03
ISSUE: 01
PAGES: 69-72
AUTHOR: Paul S. Hodgkins, John A Blair
ADDRESS: Present address: Maryland Psychiatric Research Center, University
of Maryland School of Medicine, PO Box 21247, , Baltimore, 21228, USA.
Pharmaceutical and Biological Sciences Department, Aston University, Aston
Triangle,, Birmingham, B4 7ET, UK
ABSTRACT: Correspondence to:John Blair,Pharmaceutical and Biological
Sciences Department, Aston University, Aston Triangle,Birmingham,B4
7ET,UKIron is an essential element for humans, however dysregulation of iron
metabolism can lead to several clinically recognised diseases, including
severe neurological disorders. Peripheral measurements of iron, ferritin,
and transferrin saturation in Alzheimer's disease and Down syndrome patients
clearly match the biochemical profile of patients with the iron overload
disorder haemochromatosis, and identifies a dysfunction in iron metabolism.
Brain iron concentrations are raised in Alzheimer's disease and its
distribution parallels affected brain areas. The chronic build up of iron in
the brain may be causally related to the reported neurotoxicity of this
element and ultimately result in the neuropathology associated with
Alzheimer's disease. Potential therapies which involve iron chelation may
provide an effective treatment in such cases.
KEYWORDS: Alzheimer's disease Brain Iron Model Oxidation Transferrin
J Neurochem 2000 Jul;75(1):314-20
Beneficial effects of dietary restriction on cerebral cortical synaptic
terminals: preservation of glucose and glutamate transport and mitochondrial
function after exposure to amyloid beta-peptide, iron, and 3-nitropropionic
acid.
Guo Z, Ersoz A, Butterfield DA, Mattson MP
Sanders-Brown Research Center on Aging. Department of Chemistry and
Center of Membrane Sciences, University of Kentucky, Lexington,
Kentucky, USA.
Recent studies have shown that rats and mice maintained on a dietary
restriction (DR) regimen exhibit increased resistance of neurons to
excitotoxic, oxidative, and metabolic insults in experimental models
of Alzheimer's, Parkinson's, and Huntington's diseases and stroke.
Because synaptic terminals are sites where the neurodegenerative
process may begin in such neurodegenerative disorders, we determined
the effects of DR on synaptic homeostasis and vulnerability to
oxidative and metabolic insults. Basal levels of glucose uptake were
similar in cerebral cortical synaptosomes from rats maintained on DR
for 3 months compared with synaptosomes from rats fed ad libitum.
Exposure of synaptosomes to oxidative insults (amyloid beta-peptide
and Fe(2+)) and a metabolic insult (the mitochondrial toxin
3-nitropropionic acid) resulted in decreased levels of glucose uptake.
Impairment of glucose uptake following oxidative and metabolic insults
was significantly attenuated in synaptosomes from rats maintained on
DR. DR was also effective in protecting synaptosomes against oxidative
and metabolic impairment of glutamate uptake. Loss of mitochondrial
function caused by oxidative and metabolic insults, as indicated by
increased levels of reactive oxygen species and decreased
transmembrane potential, was significantly attenuated in synaptosomes
from rats maintained on DR. Levels of the stress proteins HSP-70 and
GRP-78 were increased in synaptosomes from DR rats, consistent with
previous data suggesting that the neuroprotective mechanism of DR
involves a "preconditioning" effect. Collectively, our data provide
the first evidence that DR can alter synaptic homeostasis in a manner
that enhances the ability of synapses to withstand adversity.
PMID: 10854276, UI: 20312884
_________________________________________________________________
Am J Med Genet 2000 Jul 3;93(1):58-66
Are hereditary hemochromatosis mutations involved in Alzheimer disease?
Moalem S, Percy ME, Andrews DF, Kruck TP, Wong S, Dalton AJ, Mehta P, Fedor
B, Warren AC
Department of Physiology, University of Toronto, Toronto, ON, Canada.
Mutations in the class I-like major histocompatibility complex gene
called HFE are associated with hereditary hemochromatosis (HHC), a
disorder of excessive iron uptake. We screened DNA samples from
patients with familial Alzheimer disease (FAD) (n = 26), adults with
Down syndrome (DS) (n = 50), and older (n = 41) and younger (n = 52)
healthy normal individuals, for two HHC point mutations-C282Y and
H63D. Because the apolipoprotein E (ApoE) E4 allele is a risk factor
for AD and possibly also for dementia of the AD type in DS, DNA
samples were also ApoE genotyped. Chi-squared analyses were
interpreted at the 0.05 level of significance without Bonferroni
corrections. In the pooled healthy normal individuals, C282Y was
negatively associated with ApoE E4, an effect also apparent in
individuals with DS but not with FAD. Relative to older normals, ApoE
E4 was overrepresented in both males and females with FAD, consistent
with ApoE E4 being a risk factor for AD; HFE mutations were
overrepresented in males and underrepresented in females with FAD.
Strong gender effects on the distribution of HFE mutations were
apparent in comparisons among ApoE E4 negative individuals in the FAD
and healthy normal groups (P < 0.002). Our findings are consistent
with the proposition that among ApoE E4 negative individuals HFE
mutations are predisposing to FAD in males but are somewhat protective
in females. Further, ApoE E4 effects in our FAD group are strongest in
females lacking HFE mutations. Relative to younger normals there was a
tendency for ApoE E4 and H63D to be overrepresented in males and
underrepresented in females with DS. The possibility that HFE
mutations are important new genetic risk factors for AD should be
pursued further. Copyright 2000 Wiley-Liss, Inc.
PMID: 10861683, UI: 20321357
_________________________________________________________________
Subject: zinc/histamine/iron/alzheimer
Schweiz Arch Neurol Psychiatr 1990;141(6):523-56
[Alzheimer's dementia and zinc].
[Article in French]
Constantinidis J
Universite de Geneve, Suisse.
In Alzheimer's dementia (AD) the Primum Movens is Amyloid (AM)
production on precapillaries: Dyshoric Angiopathy, and capillaries:
Senile Plaques (SP) producing Blood-Brain-Barrier (BBB) disturbances,
entry in the brain of toxic metals which displace the zinc. Cerebral
AM alone may be asymptomatic. Clinical symptoms (Amnesia, Instrumental
Disorders) appear when AM induces Neighbouring neuritic alterations:
Paired Hellical Filaments (PHF) and Distant neuronal body lesions:
Neurofibrillary Tangles (NFT). The AM is coded by a locus on the
chromosome 21 and a duplication of this locus should be the etiology
of cerebral AM in AD. In AD cerebral zinc decreases particularly in
the hippocampus. The zinc-enzyme Superoxyde-Dismutase (SOD) is coded
by a locus also on the chromosome 21 near AM and the plasma level of
SOD is high in AD. Zinc deposits observed in capillary AM-SP, result
probably from the excess of plasmatic SOD. Other metals: Iron,
aluminium are also observed in the AM-SP and their excess in the brain
may be related to the decrease of zinc by metal to metal displacement.
The decrease of functional zinc in the brain may interfere in the
pathogenesis of PHF-NFT by metalotoxicity, neighbouring and distant to
AM. Without AM, NFT are produced also by metalotoxicity and therefore
brain zinc displacement. a) by lead: Encephalopathia saturnica b) by
many metals: Guam Encephalopathy c) by aluminium d) by BBB
disturbances leading probably to an abnormal entry of metals in the
brain (Dementia Pugilistica, viral encephalitides). NFT may be
produced by the deficiency of the following zinc enzymes: 1. Those of
DNA metabolism, indicating abnor (HOME) mal DNA and therefore abnormal protein
synthesis: PHF-NFT. 2. Those of neuronal detoxication: SOD, Carbonic
Anhydrase, Lactate Dehydrogenase leading to neuronal toxicity
particularly in the hippocampus normally rich in SOD. 3. Of Glutamate
(GLU) Dehydrogenase (GDH) resulting in an excitotoxic increase of GLU.
4. Those of the metabolism of neurotransmitters (NT): neuropeptides,
Histamine, GABA, Acetylcholine. Therapeutic proposition: a zinc
complex crossing the BBB should be useful a) to prevent that the AM
produces PHF-NFT by Neighbouring and Distant metalotoxicity and DNA
changes; b) to regularise zinc-enzymes of neuronal detoxification and
of neurotransmitters metabolisms. Preliminary trials by zinc Aspartate
give yet promising results.
Publication Types:
* Review
* Review, tutorial
PMID: 1705360, UI: 91149894
_________________________________________________________________
Yip R, Reeves JD, Lonnerdal B, et al., "Does Iron Supplementation
Compromise Zinc Nutrition in Healthy Infants?", (Oct 1985), The
American Journal of Clinical Nutrition, 42 (4), pp: 683-7.
_________________________________________________________________
Subject: zinc/DNA/iron
_________________________________________________________________
J. Biol. Chem. 271: 5125-5130 (1996)[96214945]
In vivo and in vitro iron-replaced zinc finger generates free radicals and
causes DNA damage.
D. Conte, S. Narindrasorasak & B. Sarkar
Department of Biochemistry Research, The Hospital for Sick Children,
Toronto, Ontario M5G 1X8, Canada.
The estrogen receptor (ER) is a ligand-activated transcription factor
whose DNA-binding domain (ERDBD) has eight cysteines, which coordinate
two zinc atoms, forming two zinc finger-like structures. We
demonstrate the capability of iron to replace zinc in zinc finger
(hereby referred to as iron finger) both in vivo (using Escherichia
coli BL21 (DE3)) and in vitro. Iron has the ability to substitute for
zinc in the ERDBD as demonstrated by mobility shift and methylation
interference assays of iron finger, which show specific recognition of
the estrogen response element. The DNA binding constants for both in
vivo and in vitro iron-replaced zinc fingers were similar to that of
the native finger. Atomic absorption analysis revealed a ratio of 2:1
iron atoms/mol of ERDBD protein, as found for zinc in the crystal
structure of native ERDBD. More importantly, we demonstrate that iron
finger in the presence of H2O2 and ascorbate generates highly reactive
free radicals, causing a reproducible cleavage pattern to the
proximate DNA, the estrogen response element. The deoxyribose method,
used to detect free radical species generated, and the resultant
cleaved DNA ends, caused by iron finger, suggest that the free
radicals generated are hydroxyl radicals. Due to the close proximity
of the zinc finger to DNA, we postulate that iron-substituted zinc
finger may generate free radicals while bound to genetic regulatory
response elements, leading to adverse consequences such as
iron-induced toxicity and/or carcinogenesis.
MeSH Terms:
* Base Sequence
* Cloning, Molecular
* Comparative Study
* DNA Damage*
* DNA-Binding Proteins/metabolism
* DNA-Binding Proteins/biosynthesis
* DNA, Bacterial/metabolism
* DNA, Bacterial/chemistry
* Escherichia coli/metabolism
* Escherichia coli/growth & development
* Free Radicals/metabolism
* Human
* Iron/pharmacology
* Kinetics
* Methylation
* Models, Molecular
* Molecular Sequence Data
* Nucleic Acid Conformation
* Oligodeoxyribonucleotides
* Protein Structure, Secondary
* Receptors, Estrogen/metabolism
* Receptors, Estrogen/biosynthesis
* Recombinant Proteins/metabolism
* Recombinant Proteins/biosynthesis
* Support, Non-U.S. Gov't
* Time Factors
* Zinc/physiology
* Zinc Fingers*
Substances:
* Zinc
* Iron
* Recombinant Proteins
* Receptors, Estrogen
* Oligodeoxyribonucleotides
* Free Radicals
* DNA, Bacterial
* DNA-Binding Proteins
_________________________________________________________________
Subject: zinc/iron
_________________________________________________________________
Effects of Trace Elements Supplementation on Measures of Nutritional Status
Effects of supplementation with zinc (30.4 mg/d), copper (3.4 mg/d),
and chromium (241 ug/d) on alkaline phosphatase, serum ferritin,
hemoglobin, and plasma and erythrocyte copper, iron, and zinc were
examined in apparently healthy adults over the age of 50. Differences
were found between males and females within supplement groups. Serum
ferritin decreased significantly during and following zinc
supplementation in males. Total hemoglobin increased significantly
from baseline to four weeks post supplementation in chromium and
copper supplemented females. Alkaline phosphatase decreased from
baseline to four weeks post supplementation in all groups. The
decrease was significant in the mineral supplement groups except for
females receiving zinc--but not in the placebo group. Plasma zinc
increased significantly in zinc supplemented males and during
supplementation and in copper supplemented females from the end of
supplementation to four weeks post supplementation. In the copper
group, plasma copper decreased during supplementation in females but
was not significantly different over time in males, while in the
chromium supplemented females plasma copper increased at eight weeks
of supplementation. These results support the importance of examining
the interactive effects of minerals in both males and females.
Sponsor: Agricultural Experiment Station
PI: Andrea Arquitt
_________________________________________________________________
Subject: iron/alzheimer/oxidation
Free Radic Res 2000 Feb;32(2):103-14
Time-course of oxidation of lipids in human cerebrospinal fluid in vitro.
Arlt S, Finckh B, Beisiegel U, Kontush A
Medical Clinic, University Hospital Eppendorf, Hamburg, Germany.
Oxidative mechanisms play an important role in the pathogenesis of
Alzheimer's disease, Parkinson's disease and other neurodegenerative
diseases. To assess whether the oxidation of brain lipoproteins plays
a role in the development of these pathologies, we investigated
whether the lipoproteins of human cerebrospinal fluid (CSF) are
susceptible to oxidative modification in vitro. We studied oxidation
time-course for up to 100 h of human CSF in the absence
(autooxidation) or presence of exogenous oxidants. Autooxidation of
diluted CSF was found to result in a slow accumulation of lipid
peroxidation products. The time-course of lipid hydroperoxide
accumulation revealed three consecutive phases, lag-phase, propagation
phase and plateau phase. Qualitatively similar time-course has been
typically found in human plasma and plasma lipoproteins. Autooxidation
of CSF was accelerated by adding exogenous oxidants, delayed by adding
antioxidants and completely inhibited by adding a chelator of
transition metal ions. Autooxidation of CSF also resulted in the
consumption of endogenous ascorbate, alpha-tocopherol, urate and
linoleic and arachidonic acids. Taking into account that (i) lipid
peroxidation products measured in our study are known to be derived
from fatty acids, and (ii) lipophilic antioxidants and fatty acids
present in CSF are likely to be located in CSF lipoproteins, we
conclude that lipoproteins of human CSF are modified in vitro during
its autooxidation. This autooxidation appears to be catalyzed by
transition metal ions, such as Cu(II) and Fe(III), which are present
in native CSF. These data suggest that the oxidation of CSF
lipoproteins might occur in vivo and play a role in the pathogenesis
of neurodegenerative diseases.
PMID: 10653481, UI: 20117206
_________________________________________________________________
Save the above report in [Macintosh] [Text] format
Order documents on this page through Loansome Doc
_________________________________________________________________
Subject: alzheimers/chelation
J Struct Biol 2000 Jun;130(2-3):209-16 Related Articles, Books,
LinkOut
Chelation and intercalation: complementary properties in a compound
for the treatment of Alzheimer's disease.
Cherny RA, Barnham KJ, Lynch T, Volitakis I, Li QX, McLean CA,
Multhaup G, Beyreuther K, Tanzi RE, Masters CL, Bush AI
The Department of Pathology, The University of Melbourne, Melbourne,
Victoria, 3010, Australia.
[Medline record in process]
Selective application of metal chelators to homogenates of human
Alzheimer's disease (AD) brain has led us to propose that the
architecture of aggregated beta-amyloid peptide, whether in the form
of plaques or soluble oligomers, is determined at least in part by
high-affinity binding of transition metals, especially copper and
zinc. Of the two metals, copper is implicated in reactive oxygen
species generating reactions, while zinc appears to be associated with
conformational and antioxidant activity. We tested the copper
chelators trientine, penicillamine, and bathophenanthroline for their
ability to mobilize brain Abeta as measured against our benchmark
compound bathocuproine (BC). All of these agents were effective in
solubilizing brain Abeta, although BC was the most consistent across
the range of AD brain tissue samples tested. Similarly, all of the
copper chelators depleted copper in the high-speed supernatants. BC
alone had no significant effect upon zinc levels in the soluble
fraction. BC extraction of brain tissue from C100 transgenic mice
(which express human Abeta but do not develop amyloid) revealed
SDS-resistant dimers as Abeta was mobilized from the sedimentable to
the soluble fraction. NMR analysis showed that, in addition to its
copper chelating properties, BC interacts with Abeta to form a complex
independent of the presence of copper. Such hybrid copper chelating
and "chain breaking" properties may form the basis of a rational
design for a therapy for Alzheimer's disease. Copyright 2000 Academic
Press.
PMID: 10940226, UI: 20400070
(HOME)