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*
Laboratory for Oxidation Biology, Genetics and Aging Unit, Departments of Psychiatry and
Neurology, Harvard Medical School, Massachusetts General Hospital, Charleston, MA 02129
3To whom correspondence should be addressed.
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ABSTRACT |
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 TOP ABSTRACT INTRODUCTIONPathophysiology of...Zinc supplementation for...REFERENCES |
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-helical structure of Aß, and is reversible with
chelation. In addition, Aß produces hydrogen peroxide in a
Cu(II)/Fe(III)-dependent manner, and the hydrogen peroxide formation is
quenched by Zn(II). Moreover, zinc preserves the nontoxic properties of
Aß. Although the zinc-binding proteins apolipoprotein E 
4
allele and 2-macroglobulin have been characterized as
two genetic risk factors for AD, zinc exposure as a risk factor for AD
has not been rigorously studied. Based on our findings, we envisage
that zinc may serve twin roles by both initiating amyloid deposition
and then being involved in mechanisms attempting to quench oxidative
stress and neurotoxicity derived from the amyloid mass. Hence, it
remains debatable whether zinc supplementation is beneficial or
deleterious for AD until additional studies clarify the issue.
KEY WORDS: • Alzheimer’s disease • amyloid precursor protein • Aß amyloid • zinc • homeostasis
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INTRODUCTION |
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TOPABSTRACTINTRODUCTIONPathophysiology of...Zinc supplementation for...REFERENCES |
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Pathophysiology of Alzheimer’s disease |
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TOPABSTRACTINTRODUCTIONPathophysiology of...Zinc supplementation for...REFERENCES |
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). The majority of AD cases are sporadic, 5 to 10% of
patients have familial AD (FAD) with an autosomal dominant inheritance
pattern. Alzheimer’s disease is characterized pathologically by the
accumulation of Aß-amyloid protein, neurofibrillary tangles and
neuropil threads in postmortem brains of AD patients (Glenner and Wong 1984
, Masters et al. 1985
).
Aß (39–43 amino acid residues, 
4 kDa) is the main constituent of
both senile plaques and cerebrovascular amyloid deposits
(Glenner and Wong 1984
, Masters et al. 1985
). Soluble Aß is found in the cerebrospinal fluid (CSF)
and is produced (Haass et al. 1992
, Seubert et al. 1992
) by constitutive cleavage of its transmembrane parent
molecule, the amyloid protein precursor (APP) (Kang et al. 1987
, Robakis et al. 1987
, Tanzi et al. 1987
). Amyloid protein precursor is a member of the
alternatively spliced, type 1 integral membrane glycoprotein family, of
unknown function, that are ubiquitously expressed (Tanzi et al. 1988
). Unknown proteases cleave APP to produce a mixture of
Aß peptides with carboxyl-terminal heterogeneity: Aß1-40 is the
major soluble Aß species and is found in the CSF at low nanomolar
concentrations (Vigo-Pelfrey et al. 1993
); Aß1-42 is a
minor Aß species but more fibrillogenic than Aß1-40 and is heavily
enriched in interstitial plaque amyloid (Prelli et al. 1988
).
It is generally accepted that Aß peptide is neurotoxic in
micromolar concentrations depending on its conformational state
(Lorenzo and Yankner, 1994
, Pike et al. 1991
). However, the etiopathology of AD remains unknown. The
pathologic mutations of APP in chromosome 21 indicate that abnormal
Aß and APP metabolism may give rise to the disease
(Chartier-Harlin et al. 1991
, Murrell et al. 1991
). Furthermore, inheritance of mutations in chromosome 14
(presenilin-1; Sherrington et al. 1995
) or chromosome 1 (presenilin-2;
Levy-Lahad et al. 1995
) produce the more aggressive
(early-onset) form of the disease. Moreover, apolipoprotein (apo) E
4 allele on chromosome 19 has been identified as a risk factor for
late-onset AD (Saunders et al. 1993
). More recently,
a genetic lesion on chromosome 12 was discovered to be another risk
factor for AD (Blacker et al. 1998
). The genetic lesion
is a deletion with the 2-macroglobulin (A2M)
gene that codes for A2M, a zinc-binding protein that is a major
ligand for the LDL receptor–related protein (LRP) that accumulates in
senile plaques (Du et al. 1997
, Rebeck et al. 1995
). These observations further confirm the proximity of Aß
deposition to the pathogenesis of the disorder. However, the fact that
so many proteins can influence Aß metabolism indicates that AD
pathology can be brought about by heterogeneous neurochemical
interactions.
Elucidation of the neurochemical reactions that lead to Aß amyloid
deposition should yield important insights into the hierarchy of
pathophysiological events in AD. A systematic review and appraisal of
the solubility properties of the different Aß peptide species in
various neurochemical environments have been conducted to elucidate
factors leading to amyloid plaque formation. The in vitro solubility of
synthetic Aß1-42, in neutral aqueous solutions, is less than that of
Aß1-39 and Aß1-40 (Hilbich et al. 1991
).
Soluble Aß1-39/40 can be destabilized by seeding with Aß1-42
fibrils (Jarrett et al. 1993
). In addition,
Aß1-42 is enriched in amyloid plaque cores from AD patients. Indeed,
increasing evidence suggests that heightened levels of Aß1-42
accelerate amyloid deposition in FAD. The FAD-linked APP670/671
mutation has been shown to increase the secretion of Aß species
several-fold, whereas the APP717 mutations (downstream from the
carboxyl terminus of Aß) increase the proportion of Aß1-42 produced
(Suzuki et al., 1994
). Increased soluble
Aß1-42 has also been found in the brains of individuals affected by
Down’s syndrome, a condition complicated by premature AD
(Teller et al. 1996
). Finally, the emerging consensus is
that the common effect of FAD-linked presenilin mutations is to
increase Aß1-42 production (Citron et al. 1997
,
Xia et al. 1997
).
The mere presence of Aß1-42 cannot initiate amyloid deposition
because the peptide is a normal component of healthy CSF. Several
results suggest that overproduction of Aß1-42 does not initiate
amyloid deposition in sporadic AD cases. First, Aß levels in the CSF
are not elevated in AD (Nakamura et al. 1994
,
Shoji et al. 1992
). In fact, there is evidence that
Aß1-42 levels are decreased in the CSF of AD subjects (Motter et al. 1995
). If elevated cortical Aß concentrations were
solely responsible for the initiation of amyloid, it would be difficult
to explain why the amyloid deposits are focal (related to synapses and
the cerebrovascular lamina media) and not uniform in their
distribution. Overexpression of APP and Aß species in transgenic mice
rarely results in mice bearing full AD neuropathology (Hsiao et al. 1995
), and few attempts have been successful (e.g.,
Hsiao et al. 1996
). Importantly, overexpression of
Aß1-42 from birth, which occurs in genetic forms of AD (FAD and
Down’s syndrome), does not induce amyloid deposition in childhood. In
these cases, Aß deposition still occurs in an age-dependent,
albeit accelerated manner. From these sets of observations, it seems
highly unlikely that Aß overproduction alone initiates Aß
deposition. More likely there are neurochemical factors, altered as a
stochastic consequence of aging, that initiate Aß deposition in
sporadic AD and even in FAD. One of these outstanding factors is the
abnormal interactions between Aß and cerebral biometals such as zinc.
This is because (1) there are AD-related abnormalities
in zinc homeostasis, (2) zinc is highly enriched in amyloid
plaques, (3) zinc-specific chelator can partially
solubilize human brain Aß precipitates, (4) the
interactions of Aß with zinc and other biometals can lead to its
aggregation in vitro and (5) Aß peptides display redox
activity and produce hydrogen peroxide mediated by both oxygen and
redox-active metal ions (iron and copper), which can be quenched by
Zn(II).
Cerebral zinc dyshomeostasis in Alzheimer’s disease.
Zinc, second to iron, is one of the most abundant nutritionally
essential elements in the human body (Choi and Koh 1998
). Although protein binding of zinc ions as key structure
and catalytic components has been well characterized, very little is
known about zinc homeostasis (Berg and Shi 1996
).
Several observations indicate that zinc metabolism is altered in AD,
and a growing number of reports point to an abnormality in the uptake
or distribution of zinc in AD brain causing aberrant extracellular and
intracellular levels at several brain regions (Cuajungco and Lees 1997a
, 1997b
). With a few exceptions
(Corrigan et al. 1993
, Deng et al. 1994
),
brain zinc levels have been found to be elevated in AD brain regions
such as the hippocampus (Cornett et al. 1998
,
Danscher et al. 1997
, Deibel et al. 1996
,) and amygdala (Cornett et al. 1998
,
Danscher et al. 1997
, Deibel et al. 1996
,
Lovell et al. 1998
, Samudralwar et al. 1995
, Thompson et al. 1988
). It is also the case
for neocortex where significant elevation of bulk zinc was found in
frontal, temporal, and parietal (inferior) cortices (Cornett et al. 1998
, Deibel et al. 1996
). Also, significant
elevations of zinc have been reported in the AD olfactory region
(Cornett et al. 1998
, Samudralwar et al. 1995
). In addition, there is a clear association between excess
of zinc and the formation of amyloid plaques in AD. Three separate
methods have shown markedly elevated zinc levels in the dense core
senile plaques and in vascular amyloid deposits. Constantinidis (1990
) showed this result first with histochemistry for zinc,
and it has been recently replicated using
N-(6-methoxy-8-quinolyl)-p-toluene sulphonamide
(TSQ) fluorescence, showing that both senile plaques and
angiopathic amyloid are densely filled with weakly bound zinc
(Suh et al. 1998
). Lovell et al. (1998
)
also verified that the zinc in senile plaques was enriched to
millimolar concentration.
Cellular zinc mobilization: a possible link to Alzheimer’s disease progression or amyloid deposition.
Brain zinc is turned over slowly (T1/2
= 7–42 d), with the longer half-lives in brain regions that
contain vesicular zinc (Kasarskis 1984
). Disruption of
the blood-brain barrier could result in an increased flow of zinc
into the brain (Blair-West et al. 1990
) as evidenced by
increased expression of metallothionein (MT) by reactive astrocytes
(Penkowa and Moos 1995
). It is worth noting that in AD
brain, there is a marked presence of MT-I and –II immunoreactivity
in both reactive astrocytes and microcapillaries (Zambenedetti et al. 1998
), suggesting metal- or cytokine-stimulated
overproduction, or both, in the course of the disease. Activated glial
cells are present in and around neuritic senile plaques (Wallace et al. 1997
), where interleukin (IL)-1, IL-1ß, IL-6, tumor
necrosis factor- and other cytokines have been observed to be
up-regulated in AD brains (McGeer and McGeer 1995
).
Zinc induces the release of cytokines from monocytes, a similar
response from brain glial cells induced by the regional elevation of
zinc is contemplated. In addition, hydrogen peroxide
(H2O2, 1 mmol/L) is able to
displace zinc from metalloproteins and MTs, whereas antioxidant enzymes
(catalase and superoxide dismutase) abolish dissociation of zinc from
them (Fliss and Menard 1992
).
Apoptotic cell death has been observed in the temporal lobes of AD
brains (Su et al. 1994
). It is interesting to note that
an increase in perikaryal chelatable zinc has been observed in
lymphoblasts undergoing early events of apoptosis (Zalewski et al. 1994
). It is not known whether this phenomenon is an
important event in the apoptotic death cascade and whether apoptotic
neurons will exhibit a similar effect. Nevertheless, it is known that
zinc precludes apoptotic cell death of non-neuronal cells, through
potent inhibition of a number of caspases (cysteine aspartate
proteases) (Perry et al. 1997
). Hence, influx of zinc
into neurons may be a homeostatic response to apoptotic signals.
Zinc interactions with amyloid protein precursor and Aß.
We have identified a specific and saturable binding site for zinc
(KA = 750 nmol/L) within the
cysteine-rich region on the ectodomain of APP (Bush et al. 1993
). This site has homology to all known members of the APP
superfamily (Bush et al. 1994b
), and the amyloid
precursor-like proteins 1 and 2 (APLP1 and APLP2) (Wasco et al. 1992
, 1993
). This indicates that zinc
interaction may play an important, evolutionary conserved role in APP
function and metabolism. Zinc enhances the heparin-binding affinity
of APP695 (Multhaup et al. 1994
),
enhances the inhibition of factor XIa by APP possessing the
Kunitz-type protease inhibitory insert (Komiyama et al. 1992
) and modulates the binding of APP to extracellular matrix
components (Narindrasorasak et al. 1992
). For example,
zinc (10 µmol/L) enhances the binding of laminin to three APP
isoforms by 50–100% (Narindrasorasak et al. 1992
),
whereas zinc above 50 µmol/L precipitates laminin in solution
(Ancsin and Kisilevsky 1996
). Recent studies found that
laminin inhibits Aß1-40 fibril formation, particularly when induced
by apoE-4 interaction with Aß in vitro (Bronfman et al. 1996
, Monji et al. 1998
). A key question is
whether zinc modulates laminin-mediated Aß fibril assembly. The
general view is that zinc may play a role in regulating the
adhesiveness of molecules like APP that control crucial cell-cell
and cell-matrix interactions.
It was found that Aß1-40 specifically and saturably binds zinc,
manifesting high affinity binding (KD
= 107 nmol/L) with a 1:1 (zinc/Aß) stoichiometry and low affinity
binding (KD = 5.2 µmol/L) with a 2:1
stoichiometry (Bush et al. 1994c
). This binding is
probably histidine mediated because it is abolished by acidic pH (no
binding at pH 6.0). The zinc-binding site was mapped to a stretch
of contiguous residues between positions 6 and 28 of the Aß sequence.
Occupation of the zinc-binding site, which straddles the lysine 16
position of -secretase site (Esch et al. 1990
),
inhibits -secretase type (tryptic) cleavage and so may influence the
generation of Aß from APP and may increase the biological
half-life of Aß by protecting the peptide from proteolytic attack
(Bush et al. 1994c
). Indeed, zinc has been found to
specifically inhibit the -secretase cleavage of APP (Roberts et al. 1994
). Zinc concentrations above 300 nmol/L rapidly
precipitate synthetic human Aß1-40 (Bush et al. 1994a
). Although this observation has been disputed by others
(Esler et al. 1996
), we published a confirmation, and
validation of our initial findings that as a concentration as low as 1
µmol/L zinc can induce immediate aggregation of Aß1-40
(Huang et al. 1997a
) has been confirmed
(Garzon-Rodriguez et al. 1997
). Interestingly, zinc
preserves the -helical conformation of Aß1-40, and its
complexation is completely reversed with chelation treatment
(Huang et al. 1997a
). Meanwhile, rat Aß1-40 (with
substitutions of Arg
Gly, TyrPhe and HisArg at positions 5, 10
and 13, respectively) binds zinc less avidly
(KA = 3.8 µmol/L) and is unaffected
by zinc at low concentrations, perhaps explaining the paucity with
which these animals form cerebral Aß amyloid (Shivers et al. 1988
). In the absence of zinc, the solubilities of the rat and
the human Aß species are indistinguishable (Bush et al. 1994a
). Zinc-induced Aß precipitation at pH 7.4,
confirmed by a variety of techniques, is highly specific for zinc.
Indeed, metal chelators have been found to increase resolubilization of
Aß protein from postmortem AD brain tissue (Cherny et al. 1997
).
It is believed that vesicular zinc is colocalized with glutamatergic
afferents (Beaulieu et al. 1992
), and up to 300 µmol/L
zinc could be released (Assaf and Chung 1984
) after
excitatory stimulation of hippocampal mossy fibers (Howell et al. 1984
). Although much of the released zinc must be buffered
in the extracellular environment, only ~1% of the total zinc
released after excitatory release needs to interact with Aß to induce
aggregation. Therefore, the mechanisms that exist to keep zinc and Aß
from reacting inappropriately must be close to perfectly efficient in
health but might be susceptible to homeostatic malfunction in the case
of AD. Therefore, it is imperative to delineate the upstream and
downstream events that could perturb zinc homeostasis to devise a
potential therapeutic intervention.
Synthetic Aß peptides have been shown to induce lipid
peroxidation of synaptosomes (Butterfield et al. 1994
)
and to be cytotoxic through mechanisms that involve the generation of
cellular superoxide radical (O;2>) and
H2O2 (Behl et al. 1994
, Hensley et al. 1994
), which is abolished
by superoxide dismutase (Thomas et al. 1996
) and
O;2> /H2O2
scavengers (Bruce et al. 1996
). A relationship exists
between signs of oxidative stress and the characteristic Aß
accumulation in AD brain (Hensley et al. 1995
) and
transgenic mice expressing the human Aß phenotype (Smith et al. 1998
). Emerging evidence suggests that production of
H2O2 is central to
Aß-induced cytotoxicity (Behl et al. 1994
). Recently,
we discovered that Aß directly generates
H2O2 through Cu(II)/Fe(III)
reduction, and Zn(II) quenches
H2O2 formation by Aß,
which may reflect a homeostatic mechanism to prevent excessive
H2O2 production in the
vicinity of Aß accumulation (Huang et al. 1997b
).
2-Macroglobulin: a missing link?
The A2M protein, LRP and apoE accumulate in senile plaques
(Rebeck et al. 1995
). A2M binds cytokines and
polypeptides, including Aß (Du et al. 1997
,
Hughes et al. 1998
). Studies showed that A2M/Aß
complex results in Aß degradation via LRP interaction (Narita et al. 1997
, Qiu et al. 1996
). More recently, it
was reported that A2M interaction with Aß, enhanced by the presence
of zinc, precludes its ability to form fibrillar structure and its
associated neurotoxicity in cultured cortical neurons (Du et al. 1998
, Hughes et al. 1998
). It is conceivable
that the recent report of A2M gene abnormality may be the result of
dysfunctional A2M-LRP or A2M-LRP/zinc-Aß interactions, which could
lead to AD pathogenesis through abnormal Aß clearance.
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Zinc supplementation for Alzheimer’s disease: An unresolved issue |
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TOPABSTRACTINTRODUCTIONPathophysiology of...Zinc supplementation for...REFERENCES |
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). Thus, it is not clear how one might interpret recent
evidence suggesting that dietary zinc may affect the progression of AD.
One study suggested that zinc (30 mg/kg) taken daily for 1 y
slowed the cognitive decline of AD patients (Potocnik et al. 1997
); however, the investigators studied only four patients
and there were no control groups. Another study has marshaled evidence
that zinc (400 mg/d ZnSO4), selenium (1 mg/d
Na2SeO3) and evening
primrose oil (500 mg/d, containing ~9% 
-linoleic acid and 72%
linoleic acid) significantly preserved the cognitive functions of AD
patients (Van Rhijn et al. 1990
). Prasad (1998
) presented some evidence that zinc supplementation
provides beneficial results to AD patients. Indirect effects mediated
by changes in general health may account for some of these effects.
However, zinc exposure as a risk factor for AD has not been thoroughly
examined. Our basic data lend weight to zinc being both potentially
harmful and potentially beneficial in AD. Therefore, further research
is needed to explore the true role of zinc in Aß amyloidosis of AD
and to answer the question: Is zinc supplementation beneficial or
deleterious for AD?
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FOOTNOTES |
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2 Supported by funds from the Prana Corp., National Institutes of Health (Grant R29-AG12686), Alzheimer’s Association, International Life Sciences Institute and the American Federation for Aging Research/Alliance for Aging Research (Beeson Award to A.I.B.). X.H. is a recipient of National Research Service Award from the National Institutes of Health (Grant F32-AG05782).
4 Abbreviations used: AD, Alzheimer’s disease; A2M, 2-macroglobulin; apo, apolipoprotein; APP, amyloid protein precursor; CSF, cerebrospinal fluid; FAD, familial Alzheimer’s disease; IL, interleukin; LRP, lipoprotein receptor–related protein; MT, metallothionein.
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REFERENCES |
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