Zinc, copper and iron have recently been reported to be concentrated to ... publication were Michael Hambidge, University of Colorado Health Sciences. Center ...
Zinc and Health: Current Status and Future Directions Alzheimer’s Disease, -Amyloid Protein and Zinc1,2 Xudong Huang,* Math P. Cuajungco,* Craig S. Atwood,* Robert D. Moir,† Rudolph E. Tanzi† and Ashley I. Bush*,3 *Laboratory for Oxidation Biology, Genetics and Aging Unit, Departments of Psychiatry and †Neurology, Harvard Medical School, Massachusetts General Hospital, Charleston, MA 02129 ABSTRACT Alzheimer’s disease (AD) is characterized by amyloid deposits within the neocortical parenchyma and the cerebrovasculature. The main component of these predominantly extracellular collections, A, which is normally a soluble component of all biological fluids, is cleaved out of a ubiquitously expressed parent protein, the amyloid protein precursor (APP), one of the type 1 integral membrane glycoproteins. Considerable evidence has indicated that there is zinc dyshomeostasis and abnormal cellular zinc mobilization in AD. We have characterized both APP and A as copper/zinc metalloproteins. Zinc, copper and iron have recently been reported to be concentrated to 0.5 to 1 mmol/L in amyloid plaque. In vitro, rapid A aggregation is mediated by Zn(II), promoted by the ␣-helical structure of A, and is reversible with chelation. In addition, A 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 A. 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. J. Nutr. 130: 1488S—1492S, 2000. KEY WORDS:
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Alzheimer’s disease
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amyloid precursor protein
The genetics of Alzheimer’s disease (AD)4 indicates that A amyloid deposition in the neocortex and cerebral vasculature, the pathological hallmark of the disease, is intimately involved in the pathophysiology of the disorder. However, neurochemical events that lead to the age-dependent deposition of this normally soluble component of cerebrospinal fluid
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A amyloid
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zinc
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homeostasis
are still unclear. Alzheimer’s disease is complicated by abnormalities of several neurochemical pathways. A review of the vulnerabilities of A has yielded clues as to the nature of “upstream” pathophysiological events that are the prelude to amyloid formation. Although a variety of neurochemical interactions have been proposed as responsible for A precipitation in AD, abnormal interactions between A and cerebral biometals such as zinc are outstanding candidates for further investigation as a stochastic complication of aging that affects the solubility of A. This review focuses on our recent studies on the role of zinc in Alzheimer’s A amyloidogenesis.
1 Presented at the international workshop “Zinc and Health: Current Status and Future Directions,” held at the National Institutes of Health in Bethesda, MD, on November 4 –5, 1998. This workshop was organized by the Office of Dietary Supplements, NIH and cosponsored with the American Dietetic Association, the American Society for Clinical Nutrition, the Centers for Disease Control and Prevention, Department of Defense, Food and Drug Administration/Center for Food Safety and Applied Nutrition and seven Institutes, Centers and Offices of the NIH (Fogarty International Center, National Institute on Aging, National Institute of Dental and Craniofacial Research, National Institute of Diabetes and Digestive and Kidney Diseases, National Institute on Drug Abuse, National Institute of General Medical Sciences and the Office of Research on Women’s Health). Published as a supplement to The Journal of Nutrition. Guest editors for this publication were Michael Hambidge, University of Colorado Health Sciences Center, Denver; Robert Cousins, University of Florida, Gainesville; Rebecca Costello, Office of Dietary Supplements, NIH, Bethesda, MD; and session chair, Christopher Frederickson, NeuroBio Tex, Inc., Galveston, TX. 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). 3 To whom correspondence should be addressed. 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.
Pathophysiology of Alzheimer’s disease Being the most common senile dementing disorder, AD is manifested by a graduate onset and a progressive and irreversible cognitive decline. Although the memory impairment appears in the earliest stage of the disease, patients’ motor and sensory functions are usually not affected until later stages (Cummings et al. 1998). 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 A-amyloid protein, neurofibrillary tangles and neuropil threads in postmortem brains of AD patients (Glenner and Wong 1984, Masters et al. 1985). A (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).
0022-3166/00 $3.00 © 2000 American Society for Nutritional Sciences.
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ALZHEIMER’S DISEASE, -AMYLOID PROTEIN AND ZINC
Soluble A 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 A peptides with carboxyl-terminal heterogeneity: A1-40 is the major soluble A species and is found in the CSF at low nanomolar concentrations (Vigo-Pelfrey et al. 1993); A1-42 is a minor A species but more fibrillogenic than A1-40 and is heavily enriched in interstitial plaque amyloid (Prelli et al. 1988). It is generally accepted that A 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 A 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 A deposition to the pathogenesis of the disorder. However, the fact that so many proteins can influence A metabolism indicates that AD pathology can be brought about by heterogeneous neurochemical interactions. Elucidation of the neurochemical reactions that lead to A 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 A peptide species in various neurochemical environments have been conducted to elucidate factors leading to amyloid plaque formation. The in vitro solubility of synthetic A1-42, in neutral aqueous solutions, is less than that of A1-39 and A1-40 (Hilbich et al. 1991). Soluble A1-39/40 can be destabilized by seeding with A1-42 fibrils (Jarrett et al. 1993). In addition, A1-42 is enriched in amyloid plaque cores from AD patients. Indeed, increasing evidence suggests that heightened levels of A1-42 accelerate amyloid deposition in FAD. The FAD-linked APP670/671 mutation has been shown to increase the secretion of A species several-fold, whereas the APP717 mutations (downstream from the carboxyl terminus of A) increase the proportion of A1-42 produced (Suzuki et al., 1994). Increased soluble A1-42 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 A1-42 production (Citron et al. 1997, Xia et al. 1997). The mere presence of A1-42 cannot initiate amyloid deposition because the peptide is a normal component of healthy CSF. Several results suggest that overproduction of A1-42 does not initiate amyloid deposition in sporadic AD cases. First, A levels in the CSF are not elevated in AD (Nakamura et al. 1994, Shoji et al. 1992). In fact, there is evidence that A1-42 levels are decreased in the CSF of AD subjects (Motter et al. 1995). If
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elevated cortical A 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 A 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 A1-42 from birth, which occurs in genetic forms of AD (FAD and Down’s syndrome), does not induce amyloid deposition in childhood. In these cases, A deposition still occurs in an age-dependent, albeit accelerated manner. From these sets of observations, it seems highly unlikely that A overproduction alone initiates A deposition. More likely there are neurochemical factors, altered as a stochastic consequence of aging, that initiate A deposition in sporadic AD and even in FAD. One of these outstanding factors is the abnormal interactions between A 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 A precipitates, (4) the interactions of A with zinc and other biometals can lead to its aggregation in vitro and (5) A 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-methoxy8-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
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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 metalor 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-1, 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 A. 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 heparinbinding 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 mol/L) enhances the binding of laminin to three APP isoforms by 50 –100% (Narindrasorasak et al. 1992), whereas zinc above 50 mol/L precipitates laminin in solution (Ancsin and Kisilevsky 1996). Recent studies found that laminin inhibits A1-40 fibril formation, particularly when induced by apoE-⑀4 interaction with A in vitro (Bronfman et al. 1996, Monji et al. 1998). A key question is whether zinc modulates laminin-mediated A 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 A1-40 specifically and saturably binds zinc, manifesting high affinity binding (KD ⫽ 107 nmol/L) with a 1:1 (zinc/A) stoichiometry and low affinity binding (KD ⫽ 5.2 mol/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 zincbinding site was mapped to a stretch of contiguous residues between positions 6 and 28 of the A 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 A from APP and may increase the biological half-life of A 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 con-
centrations above 300 nmol/L rapidly precipitate synthetic human A1-40 (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 mol/L zinc can induce immediate aggregation of A1-40 (Huang et al. 1997a) has been confirmed (Garzon-Rodriguez et al. 1997). Interestingly, zinc preserves the ␣-helical conformation of A1-40, and its complexation is completely reversed with chelation treatment (Huang et al. 1997a). Meanwhile, rat A1-40 (with substitutions of Arg3 Gly, Tyr3 Phe and His3 Arg at positions 5, 10 and 13, respectively) binds zinc less avidly (KA ⫽ 3.8 mol/L) and is unaffected by zinc at low concentrations, perhaps explaining the paucity with which these animals form cerebral A amyloid (Shivers et al. 1988). In the absence of zinc, the solubilities of the rat and the human A species are indistinguishable (Bush et al. 1994a). Zinc-induced A 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 A 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 mol/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 A to induce aggregation. Therefore, the mechanisms that exist to keep zinc and A 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 A 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 (O2. ) and H2O2 (Behl et al. 1994, Hensley et al. 1994), which is abolished by superoxide dismutase (Thomas et al. 1996) and O2. /H2O2 scavengers (Bruce et al. 1996). A relationship exists between signs of oxidative stress and the characteristic A accumulation in AD brain (Hensley et al. 1995) and transgenic mice expressing the human A phenotype (Smith et al. 1998). Emerging evidence suggests that production of H2O2 is central to A-induced cytotoxicity (Behl et al. 1994). Recently, we discovered that A directly generates H2O2 through Cu(II)/Fe(III) reduction, and Zn(II) quenches H2O2 formation by A, which may reflect a homeostatic mechanism to prevent excessive H2O2 production in the vicinity of A 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 A (Du et al. 1997, Hughes et al. 1998). Studies showed that A2M/A complex results in A degradation via LRP interaction (Narita et al. 1997, Qiu et al. 1996). More recently, it was reported that A2M interaction with A, 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-A interactions, which could lead to AD pathogenesis through abnormal A clearance.
ALZHEIMER’S DISEASE, -AMYLOID PROTEIN AND ZINC
Zinc supplementation for Alzheimer’s disease: An unresolved issue Brain zinc levels have been shown to be highly resistant to alteration through any dietary manipulation (Frederickson et al. 1984). 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 A amyloidosis of AD and to answer the question: Is zinc supplementation beneficial or deleterious for AD? LITERATURE CITED Ancsin, J. B. & Kisilevsky, R. (1996) Laminin interactions important for basement membrane assembly are promoted by zinc and implicate laminin zinc finger-like sequences. J. Biol. Chem. 271: 6845– 6851. Assaf, S. Y. & Chung, S. H. (1984) Release of endogenous Zn2⫹ from brain tissue during activity. Nature (Lond.) 308: 734 –736. Beaulieu, C., Dyck, R. & Cynader, M. (1992) Enrichment of glutamate in zinc-containing terminals of the cat visual cortex. Neuroreport 3: 861– 864. Behl, C., Davis, D. R., Lesley, R. & Schubert, D. (1994) Hydrogen peroxide mediates amyloid  protein toxicity. Cell 77: 817– 827. Berg, J. L. & Shi, Y. (1996) The galvanization of biology: a growing appreciation for the roles of zinc. Science (Washington, DC) 271: 1081–1085. Blacker, D., Wilcox, M. A., Laird, N. M., Rodes, L., Horvath, S. M., Go, R.C.P., Perry, R., Watson, B., Jr., Basset, S. S., McInnis, M. G., Albert, M. S., Hyman, B. T. & Tanzi, R. E. (1998) Alpha-2 macroglobulin is genetically associated with Alzheimer’s disease. Nat. Genet. 19: 357–360. Blair-West, J. R., Denton, D. A., Gibson, A. P. & McKinely, M. J. (1990) Opening the blood-brain barrier to zinc. Brain Res. 507: 6 –10. Bronfman, F. C., Garrido, J., Alvarez, A., Morgan, C. & Inestrosa, N. C. (1996) Laminin inhibits amyloid--peptide fibrillation. Neurosci. Lett. 218: 201–203. Bruce, A. J., Malfroy, B. & Baudry, M. (1996) -Amyloid toxicity in organotypic hippocampal cultures: protection by EUK-8, a synthetic catalytic free radical scavenger. Proc. Natl. Acad. Sci. U.S.A. 93: 2312–2316. Bush, A. I., Multhaup, G., Moir, R. D., Williamson, T. G., Small, D. H., Rumble, B., Pollwein, P., Beyreuther, K. & Masters, C. L. (1993) A novel zinc(II) binding site modulates the function of the A4 amyloid protein precursor of Alzheimer’s disease. J. Biol. Chem. 268: 16109 –16112. Bush, A. I., Pettingel, W. H., Multhaup, G., Paradis, M. D., Vonsattel, J. P., Gusella, J. F., Beyreuther, K., Masters, C. L. & Tanzi, R. E. (1994a) Rapid induction of Alzheimer A amyloid formation by zinc. Science (Washington, DC) 265: 1467. Bush, A. I., Pettingel, W. H., Paradis, M. D. & Tanzi, R. E. (1994c) Modulation of A adhesiveness and ␣-secretase site cleavage by zinc. J. Biol. Chem. 269: 12158. Bush, A. I., Pettingel, W. H., Paradis, M. D., Tanzi, R. E. & Wasco, W. (1994b) The amyloid -protein precursor and its mammalian homologues. J. Biol. Chem. 269: 26618 –26621. Butterfield, D. A., Hensley, K., Harris, M., Mattson, M. P. & Carney, J. M. (1994) -Amyloid peptide free radical fragments initiate synaptosomal lipoperoxidation in a sequence-specific fashion: implications to Alzheimer’s disease. Biochem. Biophys. Res. Commun. 200: 710 –715. Chartier-Harlin, M. C., Crawford, F. & Houlden, H. (1991) Early-onset Alzheimer’s disease caused by mutations at codon 717 of the -amyloid precursor protein gene. Nature (Lond.) 353: 844 – 846. Cherny, R. A., Masters, C. L., Beyreuther, K., Fairlie, D., Tanzi, R. E. & Bush, A. I. (1997) The aggregation of A in human brain is mediated by zinc. Soc. Neurosci. Abstr. 23: 534. Choi, D. W. & Koh, J. Y. (1998) Zinc and brain injury. Annu. Rev. Neurosci. 21: 347–375. Citron, M., Westaway, D., Xia, W., Carlson, G., Diehl, T., Levesque, G., JohnsonWood, K., Lee, M., Seubert, P., David, A., Kholodenko, D., Motter, R., Sherrington, R., Perry, B., Yao, H., Strome, R., Lieberburg, I., Rommens, J., Kim, S., Schenk, D., Fraser, P., St. George-Hyslop, P. H. & Selkoe, D. J. (1997) Mutant
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(1998) ␣2-Macroglobulin attenuates -amyloid peptide 1-40 fibril formation and associated neurotoxicity in cultured fetal rat cortical neurons. J. Neurochem. 70: 1182–1188. Du, Y., Ni, B. F., Glinn, M., Dodel, R. C., Bales, K. R., Zhang, Z., Hyslop, P. A. & Paul, S. M. (1997) ␣2-Macroglobulin as a -amyloid peptide-binding plasma protein. J. Neurochem. 69: 299 –305. Esch, F. S., Keim, P. S., Beattie, E. C., Blacher, R. W., Culwell, A. R., Oltersdorf, T., McClure, D. & Ward, P. J. (1990) Cleavage of amyloid  peptide during constitutive processing of its precursor. Science (Washington, DC) 248: 1122–1124. Esler, W. P., Stimson, E. R., Jennings, J. M., Ghilardi, J. R., Mantyh, P. W. & Maggio, J. E. (1996) Zinc-induced aggregation of human and rat -amyloid peptides in vitro. J. Neurochem. 66: 723–732. Fliss, H. & Menard, M. (1992) Oxidant-induced mobilization of zinc from metallothionein. Arch. Biochem. Biophys. 293: 195–199. Frederickson, C. J., Howell, G. & Kasarskis, E. J. 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