Relations between

Chuck Miller rellim at MAILHOST.TCS.TULANE.EDU
Fri Mar 26 20:50:51 EST 1999


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There is a lot of information on the relationship between Al and various =
dementias. There is a lot of conflicting information on the =
relationship. See the FAQ for this newsgroup to learn how to get more =
information. Here are a few references to get you started.=20
J Inorg Biochem 1998 Feb 15;69(3):171-6=20

Increased absorption of aluminium from a normal dietary intake in =
dementia.
Roberts NB, Clough A, Bellia JP, Kim JY
Department of Clinical Chemistry, Royal Liverpool University Hospital, =
UK.=20

Serum aluminium was significantly raised (p < 0.01) up to 2-3-fold, in =
patients with dementia including Alzheimers Disease (AD) 0.66 +/- 0.2 =
(mumol/l mean +/- 1 s.d.) and patients on regular aluminium hydroxide =
therapy 0.54 +/- 0.17, compared with healthy volunteers 0.21 +/- 0.13, =
although not as high as in patients with end stage renal failure on =
regular dialysis 0.88 +/- 0.42. The urine outputs (mumol/l mean +/- 1 =
s.d.) of aluminium and silicon, respectively, were also significantly =
increased up to 5-fold in dementia 2.89 +/- 1.78 (n =3D 23) and 1587 +/- =
645 (n =3D 22) and patients on regular aluminium hydroxide therapy 5.03 =
+/- 2.08 (n =3D 8) and 998 +/- 364 (n =3D 21) compared with healthy =
volunteers 0.95 +/- 0.82 (n =3D 84) and 471 +/- 332 (n =3D 114). The =
increase in urine aluminium was thus associated with a similarly marked =
increase in the output of silicon. The increased absorption of aluminium =
in dementia patients is equivalent to the intestinal loading in Aludrox =
therapy. Also silicon appears to be important in the renal excretion of =
the absorbed aluminium. Whether this is a phenomenon related to the =
elderly or the process of dementia warrants further study.=20



Brain Res 1998 Jul 13;799(1):91-6=20

Promotion of transition metal-induced reactive oxygen species formation =
by beta-amyloid.
Bondy SC, Guo-Ross SX, Truong AT
Center for Occupational and Environmental Health, Department of =
Community and Environmental Medicine, University of California Irvine, =
Irvine, CA 92697-1820, USA.=20

beta-amyloid protein appears to be involved in the neural degeneration =
associated with Alzheimer's disease. However, its mechanism of action is =
poorly understood. The ability of the neurotoxic peptide fragment =
(25-35) derived from beta-amyloid, to promote the generation of reactive =
oxygen species (ROS) by a postmitochondrial fraction (P2) derived from =
rat cerebrocortex, has been examined. The peptide fragment, when =
incubated together with P2, did not cause excess ROS formation. However, =
10 microM FeSO4 or 10 microM CuSO4 were able to enhance ROS production =
in the P2 fraction and this was increased further in the concurrent =
presence of the 25-35 fragment. The corresponding inverse sequence =
non-neurotoxic peptide (35-25) had no parallel ability to augment =
iron-stimulated ROS production suggesting a degree of specificity for =
the observed effect. There was no formation of excess ROS when the 25-35 =
peptide and 0.5 mM Al2(SO4)3 were incubated with the P2 fraction. =
However in the presence of both aluminum and iron salts together with =
the 25-35 peptide, ROS production was augmented to a level significantly =
higher than that in the absence of aluminum. Polyglutamate, a peptide =
reported to mitigate aluminum toxicity had no effect on iron-related ROS =
generation but completely prevented its further potentiation by =
aluminum. The results indicate that beta-amyloid is able to potentiate =
the free-radical promoting capacity of metal ions such as iron, copper =
and aluminum. Such potentiation may be a relevant mechanism underlying =
beta-amyloid-induced degeneration of nerve cells.=20

Occup Environ Med 1998 Sep;55(9):627-33=20

Occupational exposures to solvents and aluminium and estimated risk of =
Alzheimer's disease.
Graves AB, Rosner D, Echeverria D, Mortimer JA, Larson EB
Department of Epidemiology and Biostatistics, University of South =
Florida, Tampa 33612, USA.=20

OBJECTIVES: To study the role of occupational exposures to solvents and =
aluminium in the aetiology of Alzheimer's disease (AD). An industrial =
hygienist rated exposure. METHODS: 89 subjects diagnosed with probable =
AD were matched by age, sex, and type of informant to 89 controls. =
Subjects were identified from a large health maintenance organisation in =
Seattle, WA. A complete occupational history was obtained from spouses =
of cases and controls as well as from controls themselves. After the =
interview an industrial hygienist, blinded to case-control status, rated =
exposures. RESULTS: Non-significant associations were found between AD =
and ever having been occupationally exposed to solvents (odds ratio (OR) =
1.77, 95% confidence interval (95% CI) 0.81 to 3.90) and aluminium (OR =
1.46, 95% CI 0.62 to 3.42). Although an increasing risk was found with =
increasing number of years of exposure to solvents, there was an inverse =
association between exposure intensity and AD, and measures of =
cumulative exposure taking into account both intensity and duration of =
exposure were not significant. Analysis of the age at which half the =
cumulative exposure to solvents was achieved showed that an older age =
incurred a greater risk of AD than a younger age. However, the total =
amount of exposure carried no risk. CONCLUSIONS: The results suggest =
that lifetime occupational exposure to solvents and aluminium are not =
likely to be important risk factors for Alzheimer's disease.=20

Neurochem Res 1998 Dec;23(12):1467-76=20

Phosphorylation sensitizes microtubule-associated protein tau to =
Al(3+)-induced aggregation.
Li W, Ma KK, Sun W, Paudel HK
Bloomfield Center for Research in Aging, Lady Davis Institute for =
Medical Research, Sir Mortimer B. Davis-Jewish General Hospital, =
Montreal, Quebec, Canada.=20

In Alzheimer's disease the microtubule-associated protein tau becomes =
hyperphosphorylated and aggregates into paired helical filaments (PHFs). =
Although the biochemical basis of the aggregation of tau into PHFs is =
not very clear, Al3+ has been suggested to play some role. Previous =
studies have shown that Al3+ alters the phosphorylation state and causes =
aggregation of tau in experimental animals and cultured neurons. In this =
study Al3+ inhibited phosphorylation of tau by neuronal cdc2-like kinase =
and dephosphorylation of phosphorylated tau by phosphatase 2B. These =
inhibitions are very likely due to Al(3+)-induced aggregations of =
various proteins present in phosphorylation/dephosphorylation assay =
mixtures since Al3+ caused aggregations of all proteins examined. =
Furthermore, compared to other proteins, tau displayed only an average =
sensitivity towards Al(3+)-induced aggregation. However upon =
phosphorylation, tau's sensitivity towards Al3+ increased 3.5 fold. In =
the presence of the metal chelator EDTA, Al(3+)-induced aggregates of =
tau became soluble, whereas Al(3+)-induced phosphorylated tau aggregates =
were insoluble in the buffer containing EDTA and remained insensitive to =
proteolysis. Our data suggest that phosphorylation sensitizes tau to =
Al3+ and phosphorylated tau transforms irreversibly into a phosphatase =
and protease resistant aggregate in presence of this metal ion.=20

Biochem Soc Trans 1998 Aug;26(3):S251=20

Aluminosilicate particulate and beta-amyloid in vitro interactions: a =
model of Alzheimer plaque formation.
Evans P, Harrington C
Department of Public Health, University of Glasgow, Scotland.=20

Environ Health Perspect 1994 Nov;102(11):940-51=20

The biological speciation and toxicokinetics of aluminum.
DeVoto E, Yokel RA
Department of Environmental Sciences and Engineering, School of Public =
Health, University of North Carolina at Chapel Hill, USA.=20

This review discusses recent literature on the chemical and =
physiological factors that influence the absorption, distribution, and =
excretion of aluminum in mammals, with particular regard to =
gastrointestinal absorption and speciation in plasma. Humans encounter =
aluminum, a ubiquitous yet highly insoluble element in most forms, in =
foods, drinking water, and pharmaceuticals. Exposure also occurs by =
inhalation of dust and aerosols, particularly in occupational settings. =
Absorption from the gut depends largely on pH and the presence of =
complexing ligands, particularly carboxylic acids, with which the metal =
can form absorbable neutral aluminum species. Uremic animals and humans =
experience higher than normal body burdens of aluminum despite increased =
urinary clearance of the metal. In plasma, 80-90% of aluminum binds to =
transferrin, an iron-transport protein for which receptors exist in many =
tissue. The remaining fraction of plasma aluminum takes the form of =
small-molecule hydroxy species and small complexes with carboxylic =
acids, phosphate, and, to a much lesser degree, amino acids. Most of =
these species have not been observed in vivo but are predicted from =
equilibrium models derived from potentiometric methods and NMR =
investigations. These models predict that the major small-molecule =
aluminum species under plasma conditions are charged and hence =
unavailable for uptake into tissues.=20




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<BODY bgColor=3D#ffffff>
<DIV><FONT color=3D#000000>There is a lot of information on the =
relationship=20
between Al and various dementias. There is a lot of conflicting =
information on=20
the relationship. See the FAQ for this newsgroup to learn how to get =
more=20
information. Here are a few references to get you started. </FONT></DIV>
<DIV><EM>
<P>J Inorg Biochem</EM> 1998 Feb 15;69(3):171-6 </P>
<H2>Increased absorption of aluminium from a normal dietary intake in=20
dementia.</H2>
<H4>Roberts NB, Clough A, Bellia JP, Kim JY</H4>
<P>Department of Clinical Chemistry, Royal Liverpool University =
Hospital, UK.=20
</P>
<P>Serum aluminium was significantly raised (p &lt; 0.01) up to =
2-3-fold, in=20
patients with dementia including Alzheimers Disease (AD) 0.66 +/- 0.2 =
(mumol/l=20
mean +/- 1 s.d.) and patients on regular aluminium hydroxide therapy =
0.54 +/-=20
0.17, compared with healthy volunteers 0.21 +/- 0.13, although not as =
high as in=20
patients with end stage renal failure on regular dialysis 0.88 +/- 0.42. =
The=20
urine outputs (mumol/l mean +/- 1 s.d.) of aluminium and silicon, =
respectively,=20
were also significantly increased up to 5-fold in dementia 2.89 +/- 1.78 =
(n =3D=20
23) and 1587 +/- 645 (n =3D 22) and patients on regular aluminium =
hydroxide=20
therapy 5.03 +/- 2.08 (n =3D 8) and 998 +/- 364 (n =3D 21) compared with =
healthy=20
volunteers 0.95 +/- 0.82 (n =3D 84) and 471 +/- 332 (n =3D 114). The =
increase in=20
urine aluminium was thus associated with a similarly marked increase in =
the=20
output of silicon. The increased absorption of aluminium in dementia =
patients is=20
equivalent to the intestinal loading in Aludrox therapy. Also silicon =
appears to=20
be important in the renal excretion of the absorbed aluminium. Whether =
this is a=20
phenomenon related to the elderly or the process of dementia warrants =
further=20
study. </P><EM>
<P>&nbsp;</P>
<P>Brain Res</EM> 1998 Jul 13;799(1):91-6 </P>
<H2>Promotion of transition metal-induced reactive oxygen species =
formation by=20
beta-amyloid.</H2>
<H4>Bondy SC, Guo-Ross SX, Truong AT</H4>
<P>Center for Occupational and Environmental Health, Department of =
Community and=20
Environmental Medicine, University of California Irvine, Irvine, CA =
92697-1820,=20
USA. </P>
<P>beta-amyloid protein appears to be involved in the neural =
degeneration=20
associated with Alzheimer's disease. However, its mechanism of action is =
poorly=20
understood. The ability of the neurotoxic peptide fragment (25-35) =
derived from=20
beta-amyloid, to promote the generation of reactive oxygen species (ROS) =
by a=20
postmitochondrial fraction (P2) derived from rat cerebrocortex, has been =

examined. The peptide fragment, when incubated together with P2, did not =
cause=20
excess ROS formation. However, 10 microM FeSO4 or 10 microM CuSO4 were =
able to=20
enhance ROS production in the P2 fraction and this was increased further =
in the=20
concurrent presence of the 25-35 fragment. The corresponding inverse =
sequence=20
non-neurotoxic peptide (35-25) had no parallel ability to augment=20
iron-stimulated ROS production suggesting a degree of specificity for =
the=20
observed effect. There was no formation of excess ROS when the 25-35 =
peptide and=20
0.5 mM Al2(SO4)3 were incubated with the P2 fraction. However in the =
presence of=20
both aluminum and iron salts together with the 25-35 peptide, ROS =
production was=20
augmented to a level significantly higher than that in the absence of =
aluminum.=20
Polyglutamate, a peptide reported to mitigate aluminum toxicity had no =
effect on=20
iron-related ROS generation but completely prevented its further =
potentiation by=20
aluminum. The results indicate that beta-amyloid is able to potentiate =
the=20
free-radical promoting capacity of metal ions such as iron, copper and =
aluminum.=20
Such potentiation may be a relevant mechanism underlying =
beta-amyloid-induced=20
degeneration of nerve cells. </P><EM>
<P>Occup Environ Med</EM> 1998 Sep;55(9):627-33 </P>
<H2>Occupational exposures to solvents and aluminium and estimated risk =
of=20
Alzheimer's disease.</H2>
<H4>Graves AB, Rosner D, Echeverria D, Mortimer JA, Larson EB</H4>
<P>Department of Epidemiology and Biostatistics, University of South =
Florida,=20
Tampa 33612, USA. </P>
<P>OBJECTIVES: To study the role of occupational exposures to solvents =
and=20
aluminium in the aetiology of Alzheimer's disease (AD). An industrial =
hygienist=20
rated exposure. METHODS: 89 subjects diagnosed with probable AD were =
matched by=20
age, sex, and type of informant to 89 controls. Subjects were identified =
from a=20
large health maintenance organisation in Seattle, WA. A complete =
occupational=20
history was obtained from spouses of cases and controls as well as from =
controls=20
themselves. After the interview an industrial hygienist, blinded to =
case-control=20
status, rated exposures. RESULTS: Non-significant associations were =
found=20
between AD and ever having been occupationally exposed to solvents (odds =
ratio=20
(OR) 1.77, 95% confidence interval (95% CI) 0.81 to 3.90) and aluminium =
(OR=20
1.46, 95% CI 0.62 to 3.42). Although an increasing risk was found with=20
increasing number of years of exposure to solvents, there was an inverse =

association between exposure intensity and AD, and measures of =
cumulative=20
exposure taking into account both intensity and duration of exposure =
were not=20
significant. Analysis of the age at which half the cumulative exposure =
to=20
solvents was achieved showed that an older age incurred a greater risk =
of AD=20
than a younger age. However, the total amount of exposure carried no =
risk.=20
CONCLUSIONS: The results suggest that lifetime occupational exposure to =
solvents=20
and aluminium are not likely to be important risk factors for =
Alzheimer's=20
disease. </P><EM>
<P>Neurochem Res</EM> 1998 Dec;23(12):1467-76 </P>
<H2>Phosphorylation sensitizes microtubule-associated protein tau to=20
Al(3+)-induced aggregation.</H2>
<H4>Li W, Ma KK, Sun W, Paudel HK</H4>
<P>Bloomfield Center for Research in Aging, Lady Davis Institute for =
Medical=20
Research, Sir Mortimer B. Davis-Jewish General Hospital, Montreal, =
Quebec,=20
Canada. </P>
<P>In Alzheimer's disease the microtubule-associated protein tau becomes =

hyperphosphorylated and aggregates into paired helical filaments (PHFs). =

Although the biochemical basis of the aggregation of tau into PHFs is =
not very=20
clear, Al3+ has been suggested to play some role. Previous studies have =
shown=20
that Al3+ alters the phosphorylation state and causes aggregation of tau =
in=20
experimental animals and cultured neurons. In this study Al3+ inhibited=20
phosphorylation of tau by neuronal cdc2-like kinase and =
dephosphorylation of=20
phosphorylated tau by phosphatase 2B. These inhibitions are very likely =
due to=20
Al(3+)-induced aggregations of various proteins present in=20
phosphorylation/dephosphorylation assay mixtures since Al3+ caused =
aggregations=20
of all proteins examined. Furthermore, compared to other proteins, tau =
displayed=20
only an average sensitivity towards Al(3+)-induced aggregation. However =
upon=20
phosphorylation, tau's sensitivity towards Al3+ increased 3.5 fold. In =
the=20
presence of the metal chelator EDTA, Al(3+)-induced aggregates of tau =
became=20
soluble, whereas Al(3+)-induced phosphorylated tau aggregates were =
insoluble in=20
the buffer containing EDTA and remained insensitive to proteolysis. Our =
data=20
suggest that phosphorylation sensitizes tau to Al3+ and phosphorylated =
tau=20
transforms irreversibly into a phosphatase and protease resistant =
aggregate in=20
presence of this metal ion. </P><EM>
<P>Biochem Soc Trans</EM> 1998 Aug;26(3):S251 </P>
<H2>Aluminosilicate particulate and beta-amyloid in vitro interactions: =
a model=20
of Alzheimer plaque formation.</H2>
<H4>Evans P, Harrington C</H4>
<P>Department of Public Health, University of Glasgow, Scotland. =
</P><EM>
<P>Environ Health Perspect</EM> 1994 Nov;102(11):940-51 </P>
<H2>The biological speciation and toxicokinetics of aluminum.</H2>
<H4>DeVoto E, Yokel RA</H4>
<P>Department of Environmental Sciences and Engineering, School of =
Public=20
Health, University of North Carolina at Chapel Hill, USA. </P>
<P>This review discusses recent literature on the chemical and =
physiological=20
factors that influence the absorption, distribution, and excretion of =
aluminum=20
in mammals, with particular regard to gastrointestinal absorption and =
speciation=20
in plasma. Humans encounter aluminum, a ubiquitous yet highly insoluble =
element=20
in most forms, in foods, drinking water, and pharmaceuticals. Exposure =
also=20
occurs by inhalation of dust and aerosols, particularly in occupational=20
settings. Absorption from the gut depends largely on pH and the presence =
of=20
complexing ligands, particularly carboxylic acids, with which the metal =
can form=20
absorbable neutral aluminum species. Uremic animals and humans =
experience higher=20
than normal body burdens of aluminum despite increased urinary clearance =
of the=20
metal. In plasma, 80-90% of aluminum binds to transferrin, an =
iron-transport=20
protein for which receptors exist in many tissue. The remaining fraction =
of=20
plasma aluminum takes the form of small-molecule hydroxy species and =
small=20
complexes with carboxylic acids, phosphate, and, to a much lesser =
degree, amino=20
acids. Most of these species have not been observed in vivo but are =
predicted=20
from equilibrium models derived from potentiometric methods and NMR=20
investigations. These models predict that the major small-molecule =
aluminum=20
species under plasma conditions are charged and hence unavailable for =
uptake=20
into tissues. </P>
<P>&nbsp;</P></DIV></BODY></HTML>

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