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Vink R, Nechifor M, editors. Magnesium in the Central Nervous System [Internet]. Adelaide (AU): University of Adelaide Press; 2011.

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Magnesium in the Central Nervous System [Internet].

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Magnesium in Alzheimer’s disease

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Abstract

Alzheimer’s disease (AD) is the most common form of dementia. It is characterized by a progressive cognitive impairment clinically, and excessive deposits of aggregated amyloid-β (Aβ) peptides pathologically. Environmental factors, including nutrition and metal elements, are implicated in the pathophysiology of AD. Magnesium (Mg) affects many biochemical mechanisms vital for neuronal properties and synaptic plasticity, including the response of N-methyl D-aspartate (NMDA) receptors to excitatory amino acids, stability and viscosity of the cell membrane, and antagonism of calcium. Mg levels were found to be decreased in various tissues of AD patients and negatively correlated with clinical deterioration. Moreover, Mg was demonstrated to modulate the trafficking and processing of amyloid-β precursor protein, which plays a central role in the pathogenesis of AD. Here, we review in vitro and in vivo data that indicated a role for magnesium in many biological and clinical aspects of AD.

Alzheimer’s disease

Alzheimer’s disease (AD) is the most prevalent neurodegenerative disease in elderly people, affecting approximate 6-8% of all individuals over the age of 65 years. AD is characterized by progressive cognitive impairment and distinct neuropathological lesions in the brain, including intracellular neurofibrillary tangles, and extracellular, parenchymal and cerebrovascular senile plaques (Braak and Braak, 1991). Senile plaques are mainly constituted of a 39–42 amino acid peptide, amyloid-β protein (Aβ) (Glenner and Wong, 1984; Masters et al., 1985), which is generally accepted as being neurotoxic and playing a central role in the pathogenesis of neuronal dysfunction and synaptic failure in Alzheimer's disease (Selkoe, 1991; Hardy and Selkoe, 2002). Aβ is derived from full-length amyloid-β precursor protein (APP) (Kang et al., 1987; Qi-Takahara et al., 2005), which is a type I trans-membrane protein composed of a large extracellular domain, a short transmembrane domain, and a cytoplasmic tail, by sequential proteolytic cleavages by β-secretase and γ- secretase. The β-cleavage of APP, catalysed by the well characterized transmembrane aspartyl protease β-site APP-cleaving enzyme (BACE) (Hussain et al., 1999; Sinha et al., 1999; Yan et al., 1999; Haniu et al., 2000), cleaves APP at the NH2- terminus of the Aβ sequence (Seubert et al., 1993) to generates a soluble version of APP (sAPP) and a 99-residue COOH-terminal fragment (CTFβ or C99) which remains membrane bound.

C99 is further cleaved to release Aβ of varying lengths, predominantly Aβ40 and Aβ42 (Selkoe, 2001; Hussain et al., 1999; Price et al., 1998; Sinha et al., 1999; Christensen et al., 2004), by an atypical aspartyl protease, γ-secretase complex which contains at least four different proteins, namely Aph-1, nicastrin, presenilin, and Pen-2 (De Strooper, 2003; Edbauer et al., 2003). Proteolysis by γ-secretase is heterogeneous; most of the full-length Aβ species produced is a 40- residue peptide (Aβ40), whereas a small proportion is a 42-residue COOH-terminal variant (Aβ42) (Esler and Wolfe, 2001). However, prior processing of APP by α-secretase precludes the formation of the neurotoxic Aβ. It cuts APP within the Aβ region (between residues Lys16 and Leu17 of Aβ), generating a sAPPα and a membrane- anchored 83-residue C-terminal fragment (CTFα or C83), which is also a substrate of γ-secretase (Esch et al., 1990; Sisodia, 1992). α-Secretase is thought to be a metalloprotease, such as TNF-α converting enzyme (TACE) or a disintegrin and metalloprotease 10 (ADAM10) (Lammich et al., 1999). Secreted APP exerts proliferative actions in a variety of cell types as well as neurotropic and neuroprotective effects (Mucke et al., 1996).

Synaptic failure in AD is caused by accumulation and oligomerization of Aβ42 in limbic and association cortices (Selkoe, 2002). Mutations in the APP gene or presenilin (PS) 1 or 2 genes, which cause an autosomal dominant early onset familial AD (<5% of AD patients), increases the relative production of Aβ42 (Wiltfang et al., 2001). In the majority of patients with so-called sporadic late-onset AD, an age-dependent accumulation of Aβ, caused by disturbed dynamic balance between anabolic and catabolic activities, has been implicated (Selkoe, 1999; 2001b). Also, environmental factors, such as metallic elements may play a protective or disruptive role in the pathogenesis of AD (for review, see Adlard and Bush, 2006; Shcherbatykh and Carpenter, 2007). Different metals may be involved in multiple aspects of the disease process, such as the regulation of APP gene expression and mRNA translation, the proteolytic processing of APP, the aggregation and degradation of Aβ, and the formation of neuro- fibrillary tangles. Heavy metals (e.g. lead, mercury and cadmium) are neurotoxic and associated with intellectual impairment (Bleecker et al., 2005). Recent studies have implicated lead exposure in the subsequent elevation of APP and Aβ in animals (Basha et al., 2005b) as well as in the aggregation of synthetic Aβ1–40 in vitro (Basha et al., 2005a). In the case of aluminium, another “toxic” metal, its relevance to AD is ascribed to the involvement in the formation of paired helical filaments (PHF), the aggregation and toxicity of Aβ, and the generation of oxidative species (for review, see Gupta et al., 2005). Transition metals (e.g. copper, zinc, and iron, which are essential in cell biology) can induce Aβ aggregation (Huang et al., 2004; Mantyh et al., 1993) and are found concentrated in and around the amyloid plaques in the AD brain (Lovell et al., 1998). Disturbed homeostasis of these biometals in the AD brain (decreased copper levels, and increased concen- trations of iron, zinc, and manganese) has been reported (Cornett et al., 1998; Deibel et al., 1996). An imbalance of zinc and copper has been shown to significantly alter APP processing and Aβ generation in relevant animal models (Bayer et al., 2003; Borchardt et al., 1999; Phinney et al., 2003; Sparks and Schreurs, 2003; Lee et al., 2002; Friedlich et al., 2004).

Neurological function of magnesium

The magnesium ion, Mg2+, is the second most abundant intracellular cation, serving to stabilize nucleic acid and protein structure (Subirana et al., 2003; Brion and Westhof, 1997), and regulating over 300 enzymes as a cofactor (Romani et al., 1992; 1993; Zhao et al., 2002), including ATP- related enzymatic reactions (Hirata et al., 2002; Ko et al., 1999). Physiological concentrations of Mg are essential for synaptic conduction, and required for normal functioning of the nervous system. It has various effects at different concentrations on intellectual and neuronal functions via many bio-chemical mechanisms, including NMDA-receptor responses to excitatory amino acids and calcium influx (Nowak et al., 1984; Mayer et al., 1984; Vandenberg et al., 1987; Matsuda et al., 1987), inhibition of calcium channels (Iseri and French, 1984) and glutamate release (Lin et al., 2002), effects on cell membrane fluidity and stability (Ebel and Gunther, 1980), and toxic effects of calcium (Alvarez-Leefmans et al., 1987). These mechanisms have important roles in chronic neuronal degeneration and subsequent development of dementia.

The role of Mg in degenerative diseases has been the focus of increased attention in recent years. Continuous low Mg intake for two generations induces exclusive loss of dopaminergic neurons in rats (Oyanagi, 2005), and may support the Mg hypothesis in the pathogenesis of parkinsonism- dementia complex (PDC) of Guam. Mg supple- mentation prevents the loss of dopaminergic neurons and ameliorates neurite pathology in a PD model, indicating a role of Mg in protection of dopaminergic neurons in the substantia nigra from degeneration (Oyanagi et al., 2006; Hashimoto et al., 2008). Also, Mg at concentrations > 0.75 mM inhibits the aggregation of α-synuclein, induced either spontaneously or by incubation with iron (Golts et al., 2002). Microinjection of magnesium into cells caused microtubule disassembly (Prescott et al., 1988). Mg2+ and Ca2+ effectively induced formation of approximately 340 kD aggregates of paired helical filament tau (PHF-tau) obtained from corticobasal degeneration (CBD) and AD but not normal tau proteins isolated from fetal and adult brains, as determined by sodium dodecyl sulphate (SDS)-polyacrylamide gel electrophoresis and immunoblotting (Yang et al., 1999). This finding suggests regional elevation of these ions may trigger pathological deposition of PHF-tau in certain neurodegenerative disorders.

Magnesium in AD

Recent evidence suggests that Mg was implicated in the pathogenesis of AD. Mg levels were decreased in the serum and brain tissues of AD patients in clinical, experimental and autopsy studies (Durlach, 1990; Glick, 1990a; Lemke, 1995; Andrási et al., 2000; 2005; Vural et al., 2010). Moreover, serum Mg levels in AD patients negatively correlated with the Global Deterioration Scale (GDS) and the Clinical Dementia Rating (CDR) (Cilliler et al., 2007). A causal relationship between low Mg in hippocampal neurons and impairment of learning was also demonstrated in aged rats (Landfield et al., 1984). Magnesium deficiency can lead to specific impairments in emotional memory (Bardgett et al., 2005; Bardgett et al., 2007), while magnesium therapy facilitates cognitive function recovery following brain injury; however, there are task and dose- dependent aspects to this recovery (Enomoto et al., 2005; Hoane, 2005; Hoane, 2007). Increasing brain magnesium leads to the enhancement of both short-term synaptic facilitation and long- term potentiation and improves learning and memory functions in rats (Slutsky et al., 2010). Interestingly, treatment of dementia patients with nutritional Mg support efficiently improved memory and other symptoms (Glick et al., 1990b). However, therapeutic administration of Mg is still controversial regarding the treatment of AD, and high doses of Mg may have potential detrimental side effects (Clark and Brown, 1992; Fung et al., 1995; Hallak, 1998; Ladner and Lee, 1999).

Neuronal degeneration occurs in PS1 mutant mice without extracellular Aβ deposits, suggesting it is caused by the accumulation of intracellular Aβ42 (Chui et al., 1999). Deposits of intracellular Aβ42 are correlated with apoptotic cell death in AD brains (Chui et al., 2001). The Aβ is derived from APP through sequential cleavages by β-and γ-secretases, whose enzymatic activities are tightly controlled by subcellular localization. Thus, delineation of how the intracellular trafficking of these secretases and APP are regulated is important for understanding AD pathogenesis. Although APP trafficking is regulated by multiple factors including PS1 (Cai et al., 2003), a major component of the γ-secretase complex, and phospholipase D1, a phospholipid- modifying enzyme, APP can reciprocally regulate PS1 trafficking. APP deficiency results in faster transport of PS1 from the trans-Golgi network to the cell surface and increased steady state levels of PS1 at the cell surface, which can be reversed by restoring APP levels (Liu et al., 2009). However, it is not known whether altered magnesium level may also affect APP trafficking or/and processing. Recently, it has been demonstrated that magnesium modulated APP processing in a time- and dose-dependent manner: extracellular magnesium ([Mg2+]o) at high doses increased CTFα level and sAPPα release. In contrast, [Mg2+]o at low doses enhanced CTFβ accumulation and Aβ secretion (Yu et al., 2010). The mechanism of how varying magnesium concentrations led to shifts between α- and β-secretase cleavage of APP might be partially explained by the evidence that [Mg2+]o at high doses promoted retention of APP on plasma membrane, whereas [Mg2+]o at low doses reduced cell surface APP level (Yu et al., 2010). All APP family members are predominantly cleaved in the late secretory pathway, including the plasma membrane and endosomes (Yamazaki et al., 1996). Further, different secretase activities show distinct subcellular localization, namely α- secretase at the plasma membrane (Lammich et al., 1999; Skovronsky et al., 2000) and β/γ- secretases within endocytic compartments (Vassar et al., 1999; Huse et al., 2000 ; Cupers et al., 2001 ; Kaether et al., 2002; Ray et al., 1999). Because targeting of APP to distinct subcellular compartments determines processing into amyloidogenic or non-amyloidogenic products, much attention has been focused on factors that regulate APP trafficking. Interestingly, several adaptor proteins are known to influence APP transport and processing. For example, F- spondin, a secreted factor that binds to the extracellular domain of APP (Ho and Sudhof, 2004), has been shown to increase levels of cell surface APP, promote α-cleavage of APP, and decrease β-cleavage of APP (Hoe et al., 2005). Similarly, the extracellular matrix protein Reelin caused increased surface APP and a preference for α-cleavage over β-cleavage (Hoe et al., 2006b). These findings suggest that trafficking and proteolysis of APP are regulated together. Thus a function of [Mg2+]o in APP transport from/to the cell surface might be a possible explanation for its modulation of APP processing. In the light of Mg2+ as an antagonist of the NMDA receptor, our finding is corroborated by the previous report that chronic NMDA receptor activation decreased α-secretase-mediated APP processing and increased Aβ production in cultured cortical neurons (Lesne et al., 2005). Furthermore, several lines of evidence suggest that APP metabolism and Aβ levels are closely correlated with neural activity in animals (Fazeli et al., 1994; Turner et al., 2004; Cirrito et al., 2005; 2008) and humans (Buckner et al., 2005). It has been demonstrated that decreasing neuronal activity by high [Mg2+]o (10 mM MgCl2) resulted in significant reduction of Aβ secretion, which may involve a change in APP processing (Kamenetz et al., 2003). However, the precise functional mechanism of how magnesium regulates APP transport and whether magnesium interacts with α- and β-secretase, or regulates enzyme activity, or their subcellular localization, remains undetermined but will be part of our future analysis.

The dose dependent response of sAPPα to increasing [Mg2+]o implies high concentrations of Mg may exert protective effects against AD. Various studies have strongly established that secreted sAPPα possesses potent neurotrophic and neuroprotective activities against excitotoxic and oxidative insults (Mattson et al., 1993; Schubert et al., 1993), p53-mediated apoptosis (Xu et al., 1999), and the proapoptotic action of mutant PS1 by activating the transcription factor NF-κB (Guo et al., 1998). Moreover, sAPPα stimulates neurite outgrowth (Small et al., 1994), regulates synaptogenesis (Morimoto et al., 1998), exerts trophic effects on cerebral neurons in culture (Araki et al., 1991), stabilizes neuronal calcium homeostasis and protects hippocampal and cortical neurons against the toxic effects of glutamate and Aβ peptides (Furukawa et al., 1996). It also has been shown that intra- cerebroventricular administration of secreted forms of sAPPα to amnestic mice has potent memory-enhancing effects and blocks learning deficits induced by scopolamine (Meziane et al., 1998).

Secreted Aβ increased upon low [Mg2+]o (0.0 and 0.4 mM) compared with physiological concen- tration of Mg (i.e. 0.8 mM), whereas high [Mg2+]o (1.2, 1.6, 4.0 mM) could not significantly lower total extracellular Aβ level (Yu et al., 2010). The data are consistent with several reports showing a dissociation between sAPPα release and Aβ generation both in vitro or in vivo (Loefler and Huber, 1993; Querfurth et al., 1994; Dyrks et al., 1994; LeBlanc et al., 1998; Rossner et al., 2000), suggesting that there might be a more complex regulatory mechanism of these two processing events of APP. For instance, constitutive activation of PKC in guinea pig brain increased sAPPα secretion without any effect on secreted Aβ (Rossner et al., 2000), suggesting that the α- and β-secretase pathways may be differentially controlled. Because Yu et al., (2010) examined the effects of Mg only on the pathologically high production of Aβ, the modulation of the physiological Aβ production by Mg needs to be established in future studies. The steady-state level of Aβ peptide is determined by the rate of production from APP via β- and γ-secretases and degradation by the activity of several degradative enzymes, including neprilysin (Hama et al., 2001; Iwata et al., 2001; Shirotani et al., 2001; Leissring et al., 2003; Marr et al., 2004; review see Wang et al., 2006), insulin degrading enzyme (IDE) (Kurochkin et al., 1994; Farris et al., 2003), endothelin-converting enzyme (Eckman et al., 2003) and MMPs (Roher et al., 1994; Backstrom et al., 1996; Leissring et al., 2003). Yu et al., (unpublished data) also found that Mg deprivation resulted in a 50% decrease of neprilysin activity without alteration in the protein level of neprilysin and IDE. Thus, the exacerbated accumulation of Aβ induced by [Mg2+]o at 0.0 mM resulted from both the enhanced production and aberrant catabolism.

Conclusion

Magnesium participates in the biochemical mechanisms of neuronal properties and synaptic functions, which are involved in the patho- physiology of neurodegenerative diseases.

Magnesium was demonstrated to modulate APP trafficking and processing, and its level was found decreased in AD patients. Both clinical and experimental data implicated a role of Mg in the pathogenesis of AD. Given the prevalence of magnesium inadequacy in the general population (Ford and Mokdad, 2003), magnesium supplementation could constitute a potential novel pharmacological target for the treatment of AD via its action on APP processing.

Acknowledgement

This work was supported by the National Natural Science Foundation of China (NSFC; Grants No. 30570533, No. 30670414 and No. 30973145) and the National High Technology Research and Development Program of China (973 Program No. 2006CB500705 and 863 Program No. 0060102A4031).

References

  • Adlard PA, Bush AI. Metals and Alzheimer's disease. J Alzheimers Dis. 2006;10:145–63. [PubMed: 17119284]
  • Alvarez-Leefmans FJ, Giraldez F, Gamino SM. Intracellular free magnesium in excitable cells: its measurement and its biologic significance. Can J Physiol Pharmacol. 1987;65:915–25. [PubMed: 3113706]
  • Andrási E, Igaz S, Molnar Z, Mako S. Disturbances of magnesium concentrations in various brain areas in Alzheimer's disease. Magnes Res. 2000;13:189–96. [PubMed: 11008926]
  • Andrási E, Páli N, Molnár Z, Kösel S. Brain aluminum, magnesium and phosphorus contents of control and Alzheimer-diseased patients. J Alzheimers Dis. 2005;7:273–84. [PubMed: 16131728]
  • Araki W, Kitaguchi N, Tokushima Y, Ishii K, Aratake H, Shimohama S, Nakamura S, Kimura J. Trophic effect of beta-amyloid precursor protein on cerebral cortical neurons in culture. Biochem Biophys Res Commun. 1991;181:265–71. [PubMed: 1958195]
  • Backstrom JR, Lim GP, Cullen MJ, Tokes ZA. Matrix metalloproteinase-9 (MMP-9) is synthesized in neurons of the human hippocampus and is capable of degrading the amyloid-beta peptide (1-40). J Neurosci. 1996;16:7910–9. [PubMed: 8987819]
  • Bardgett ME, Schultheis PJ, McGill DL, Richmond RE, Wagge JR. Magnesium deficiency impairs fear conditioning in mice. Brain Res. 2005;1038:100–6. [PubMed: 15748878]
  • Bardgett ME, Schultheis PJ, Muzny A, Riddle MD, Wagge JR. Magnesium deficiency reduces fear- induced conditional lick suppression in mice. Magnes Res. 2007;20:58–65. [PubMed: 17536490]
  • Basha MR, Murali M, Siddiqi HK, Ghosal K, Siddiqi OK, Lashuel HA, Ge YW, Lahiri DK, Zawia NH. Lead (Pb) exposure and its effect on APP proteolysis and Abeta aggregation. FASEB J. 2005a;19:2083–4. [PubMed: 16230335]
  • Basha MR, Wei W, Bakheet SA, Benitez N, Siddiqi HK, Ge YW, Lahiri DK, Zawia NH. The fetal basis of amyloidogenesis: exposure to lead and latent over- expression of amyloid precursor protein and beta- amyloid in the aging brain. J Neurosci. 2005b;25:823–9. [PubMed: 15673661]
  • Bayer TA, Schafer S, Simons A, Kemmling A, Kamer T, Tepest R, Eckert A, Schussel K, Eikenberg O. Dietary Cu stabilizes brain superoxidemdismutase 1 activity and reduces amyloid Abeta production in APP23 transgenic mice. Proc Natl Acad Sci USA. 2003;100:14187–92. Sturchler- Pierrat C, Abramowski D, Staufenbiel M, Multhaup G. [PMC free article: PMC283567] [PubMed: 14617773]
  • Bleecker ML, Ford DP, Lindgren KN, Hoese VM, Walsh KS, Vaughan CG. Differential effects of lead exposure on components of verbal memory. Occup Environ Med. 2005;62:181–7. [PMC free article: PMC1740967] [PubMed: 15723883]
  • Borchardt T, Camakaris J, Cappai R, Masters CL, Beyreuther K, Multhaup G. Copper inhibits beta- amyloid production and stimulates the non- amyloidogenic pathway of amyloid-precursor-protein secretion. Biochem J. 1999;344:461–7. [PMC free article: PMC1220664] [PubMed: 10567229]
  • Braak H, Braak E. Neuropathological stageing of Alzheimer-related changes. Acta Neuropathol. 1991;82:239–59. [PubMed: 1759558]
  • Brion P, Westhof E. Hierarchy and dynamics of RNA folding. Annu Rev Biophys Biomol Struct. 1997;26:113–37. [PubMed: 9241415]
  • Buckner RL, Snyder AZ, Shannon BJ, LaRossa G, Sachs R, Fotenos AF, Sheline YI, Klunk WE, Mathis CA, Morris JC, Mintun MA. Molecular, structural, and functional characterization of Alzheimer's disease: evidence for a relationship between default activity, amyloid, and memory. J Neurosci. 2005;25:7709–17. [PubMed: 16120771]
  • Cai D, Leem JY, Greenfield JP, Wang P, Kim BS, Lopes KO, Kim SH, Zheng H. Presenilin-1 regulates intracellular trafficking and cell surface delivery of beta-amyloid precursor protein. J Biol Chem. 2003;278:3446–54. Greengard |P, Sisodia SS, Thinkaran G, Xu H. [PubMed: 12435726]
  • Christensen MA, Zhou W, Qing H, Lehman A, Philipsen S, Song W. Transcriptional regulation of BACE1, the beta-amyloid precursor protein beta-secretase, by Sp1. Mol Cell Biol. 2004;24:865–74. [PMC free article: PMC343820] [PubMed: 14701757]
  • Chui DH, Dobo E, Makifuchi T, Akiyama H, Kawakatsu S, Petit A, Checler F, Araki W, Takahashi K, Tabira T. Apoptotic neurons in Alzheimer’s disease frequently show intracellular Abeta42 labeling. J Alzheimers Dis. 2001;3:231–9. [PubMed: 12214064]
  • Chui DH, Tanahashi H, Ozawa K, Ikeda S, Checler F, Ueda O, Suzuki H, Araki W, Inoue H, Shirotani K, Takahashi K, Gallyas F, Tabira T. Transgenic mice with Alzheimer presenilin 1 mutations show accelerated neurodegeneration without amyloid plaque formation. Nat Med. 1999;5:560–64. [PubMed: 10229234]
  • Cilliler AE, Ozturk S, Ozbakir S. Serum magnesium level and clinical deterioration in Alzheimer's disease. Gerontology. 2007;53:419–22. [PubMed: 17992016]
  • Cirrito JR, Kang JE, Lee J, Stewart FR, Verges DK, Silverio LM, Bu G, Mennerick S, Holtzman DM. Endocytosis is required for synaptic activity-dependent release of amyloid-beta in vivo. Neuron. 2008;58:42–51. [PMC free article: PMC2390913] [PubMed: 18400162]
  • Cirrito JR, Yamada KA, Finn MB, Sloviter RS, Bales KR, May PC, Schoepp DD, Paul SM, Mennerick S, Holtzman DM. Synaptic activity regulates interstitial fluid amyloid-beta levels in vivo. Neuron. 2005;48:913–22. [PubMed: 16364896]
  • Clark BA, Brown RS. Unsuspected morbid hypermagnesemia in elderly patients. Am J Nephrol. 1992;12:336–43. [PubMed: 1489003]
  • Cornett CR, Markesbery WR, Ehmann WD. Imbalances of trace elements related to oxidative damage in Alzheimer’s disease brain. NeuroToxicology. 1998;19:339–45. [PubMed: 9621340]
  • Cupers P, Bentahir M, Craessaerts K, Orlans I, Vanderstichele H, Saftig P, De SB, Annaert W. The discrepancy between presenilin subcellular localization and gamma-secretase processing of amyloid precursor protein. J Cell Biol. 2001;154:731–40. [PMC free article: PMC2196466] [PubMed: 11502763]
  • De Strooper B. Aph-1, Pen-2, and Nicastrin with Presenilin generate an active gamma-Secretase complex. Neuron. 2003;38:9–12. [PubMed: 12691659]
  • Deibel MA, Ehmann WD, Markesbery WR. Copper, iron, and zinc imbalances in severely degenerated brain regions in Alzheimer’s disease: possible relation to oxidative stress. J Neurol Sci. 1996;143:137–42. [PubMed: 8981312]
  • Durlach J. Magnesium depletion and pathogenesis of Alzheimer's disease. Magnes Res. 1990;3:217–8. [PubMed: 2132752]
  • Dyrks T, Monning U, Beyreuther K, Turner J. Amyloid precursor protein secretion and beta A4 amyloid generation are not mutually exclusive. FEBS Lett. 1994;349:210–4. [PubMed: 8050568]
  • Ebel H, Gunther T. Magnesium metabolism: a review. J Clin Chem Clin Biochem. 1980;18:257–70. [PubMed: 7000968]
  • Eckman EA, Watson M, Marlow L, Sambamurti K, Eckman CB. Alzheimer's disease beta-amyloid peptide is increased in mice deficient in endothelin- converting enzyme. J Biol Chem. 2003;278:2081–4. [PubMed: 12464614]
  • Edbauer D, Winkler E, Regula JT, Pesold B, Steiner H, Haass C. Reconstitution of gamma-secretase activity. Nat Cell Biol. 2003;5:486–8. [PubMed: 12679784]
  • Enomoto T, Osugi T, Satoh H, McIntosh TK, Nabeshima T. Pre-Injury magnesium treatment prevents traumatic brain injury-induced hippocampal ERK activation, neuronal loss, and cognitive dysfunction in the radial-arm maze test. J Neurotrauma. 2005;22:783–92. [PubMed: 16004581]
  • Esch FS, Keim PS, Beattie EC, Blacher RW, Culwell AR, Oltersdorf T, McClure D, Ward PJ. Cleavage of amyloid beta peptide during constitutive processing of its precursor. Science. 1990;248:1122–4. [PubMed: 2111583]
  • Esler WP, Wolfe MS. A portrait of Alzheimer secretases--new features and familiar faces. Science. 2001;293:1449–54. [PubMed: 11520976]
  • Farris W, Mansourian S, Chang Y, Lindsley L, Eckman EA, Frosch MP, Eckman CB, Tanzi RE, Selkoe DJ, Guenette S. Insulin-degrading enzyme regulates the levels of insulin, amyloid beta-protein, and the beta-amyloid precursor protein intracellular domain in vivo. Proc Natl Acad Sci USA. 2003;100:4162–7. [PMC free article: PMC153065] [PubMed: 12634421]
  • Fazeli MS, Breen K, Errington ML, Bliss TV. Increase in extracellular NCAM and amyloid precursor protein following induction of long-term potentiation in the dentate gyrus of anaesthetized rats. Neurosci Lett. 1994;169:77–80. [PubMed: 8047297]
  • Ford ES, Mokdad AH. Dietary magnesium intake in a national sample of US adults. J Nutr. 2003;133:2879–82. [PubMed: 12949381]
  • Friedlich AL, Lee JY, van Groen T, Cherny RA, Volitakis I, Cole TB, Palmiter RD, Koh JY, Bush AI. Neuronal zinc exchange with the blood vessel wall promotes cerebral amyloid angiopathy in an animal model of Alzheimer’s disease. J Neurosci. 2004;24:3453–9. [PubMed: 15056725]
  • Fung MC, Weintraub M, Bowen DL. Hypermagnesemia. Elderly over-the-counter drug users at risk. Arch Fam Med. 1995;4:718–23. [PubMed: 7620603]
  • Furukawa K, Barger SW, Blalock EM, Mattson MP. Activation of K+ channels and suppression of neuronal activity by secreted beta-amyloid-precursor protein. Nature. 1996;379:74–78. [PubMed: 8538744]
  • Glenner GG, Wong CW. Alzheimer's disease: initial report of the purification and characterization of a novel cerebrovascular amyloid protein. Biochem Biophys Res Commun. 1984;120:885–90. [PubMed: 6375662]
  • Glick JL. Dementias: the role of magnesium deficiency and an hypothesis concerning the pathogenesis of Alzheimer's disease. Med Hypotheses. 1990a;31:211–25. [PubMed: 2092675]
  • Glick JL. Use of magnesium in the management of dementias. Med Sci Res. 1990b;18:831–3.
  • Golts N, Snyder H, Frasier M, Theisler C, Choi P, Wolozin B. Magnesium Inhibits Spontaneous and Iron-induced Aggregation of a-Synuclein. J Biol Chem. 2002;277:16116–23. [PubMed: 11850416]
  • Guo Q, Robinson N, Mattson MP. Secreted beta- amyloid precursor protein counteracts the proapoptotic action of mutant presenilin-1 by activation of NF-kappaβ and stabilization of calcium homeostasis. J Biol Chem. 1998;273:12341–51. [PubMed: 9575187]
  • Gupta VB, Anitha S, Hegde ML, Zecca L, Garruto RM, Ravid R, Shankar SK, Stein R, Shanmugavelu P, Jagannatha Rao KS. Aluminium in Alzheimer’s disease: are we still at a crossroad? Cell Mol Life Sci. 2005;62:143–58. [PubMed: 15666086]
  • Hallak M. Effect of parenteral magnesium sulfate administration on excitatory amino acid receptors in the rat brain. Magnes Res. 1998;11:117–31. [PubMed: 9675756]
  • Hama E, Shirotani K, Masumoto H, Sekine-Aizawa Y, Aizawa H, Saido TC. Clearance of extracellular and cell-associated amyloid beta peptide through viral expression of neprilysin in primary neurons. J Biochem. 2001;130:721–6. [PubMed: 11726269]
  • Haniu M, Denis P, Young Y, Mendiaz EA, Fuller J, Hui JO, Bennett BD, Kahn S, Ross S, Burgess T, Katta V, Rogers G, Vassar R, Citron M. Characterization of Alzheimer's beta -secretase protein BACE. A pepsin family member with unusual properties. J Biol Chem. 2000;275:21099–106. [PubMed: 10887202]
  • Hardy J, Selkoe DJ. The amyloid hypothesis of Alzheimer's disease: progress and problems on the road to therapeutics. Science. 2002;297:353–6. [PubMed: 12130773]
  • Hashimoto T, Nishi K, Nagasao J, Tsuji S, Oyanagi K. Magnesium exerts both preventive and ameliorating effects in an in vitro rat Parkinson disease model involving 1-methyl-4-phenylpyridinium (MPP+) toxicity in dopaminergic neurons. Brain Res. 2008;1197:143–51. [PubMed: 18242592]
  • Hirata A, Hirata F. DNA chain unwinding and annealing reactions of lipocortin (annexin) I heterotetramer: regulation by Ca(2+) and Mg(2+). Biochem Biophys Res Commun. 2002;291:205–9. [PubMed: 11846390]
  • Ho A, Sudhof TC. Binding of F-spondin to amyloid-beta precursor protein: a candidate amyloid- beta precursor protein ligand that modulates amyloid- beta precursor protein cleavage. Proc Natl Acad Sci USA. 2004;101:2548–53. [PMC free article: PMC356987] [PubMed: 14983046]
  • Hoane MR. Treatment with magnesium improves reference memory but not working memory while reducing GFAP expression following traumatic brain injury. Restor Neurol Neurosci. 2005;23:67–77. [PubMed: 15990413]
  • Hoane MR. Assessment of cognitive function following magnesium therapy in the traumatically injured brain. Magnes Res. 2007;20:229–36. [PubMed: 18271492]
  • Hoe HS, Tran TS, Matsuoka Y, Howell BW, Rebeck GW. DAB1 and Reelin effects on amyloid precursor protein and ApoE receptor 2 trafficking and processing. J Biol Chem. 2006;281:35176–85. [PubMed: 16951405]
  • Hoe HS, Wessner D, Beffert U, Becker AG, Matsuoka Y, Rebeck GW. F-spondin interaction with the apolipoprotein E receptor ApoEr2 affects processing of amyloid precursor protein. Mol Cell Biol. 2005;25:9259–68. [PMC free article: PMC1265841] [PubMed: 16227578]
  • Huang X, Moir RD, Tanzi RE, Bush AI, Rogers JT. Redox-active metals, oxidative stress, and Alzheimer’s disease pathology. Ann NY Acad Sci. 2004;1012:153–63. [PubMed: 15105262]
  • Huse JT, Pijak DS, Leslie GJ, Lee VM, Doms RW. Maturation and endosomal targeting of beta-site amyloid precursor protein-cleaving enzyme. The Alzheimer's disease beta-secretase. J Biol Chem. 2000;275:33729–37. [PubMed: 10924510]
  • Hussain I, Powell D, Howlett DR, Tew DG, Meek TD, Chapman C, Gloger IS, Murphy KE, Southan CD, Ryan DM, Smith TS, Simmons DL, Walsh FS, Dingwall C, Christie G. Identification of a novel aspartic protease (Asp 2) as β-secretase. Mol Cell Neurosci. 1999;14:419–27. [PubMed: 10656250]
  • Iseri LT, French JH. Magnesium: nature's physiologic calcium blocker. Am Heart J. 1984;108:188–193. [PubMed: 6375330]
  • Iwata N, Tsubuki S, Takaki Y, Shirotani K, Lu B, Gerard NP, Gerard C, Hama E, Lee HJ, Saido TC. Metabolic regulation of brain Abeta by neprilysin. Science. 2001;292:1550–2. [PubMed: 11375493]
  • Kaether C, Lammich S, Edbauer D, Ertl M, Rietdorf J, Capell A, Steiner H, Haass C. Presenilin-1 affects trafficking and processing of betaAPP and is targeted in a complex with nicastrin to the plasma membrane. J Cell Biol. 2002;158:551–61. [PMC free article: PMC2173840] [PubMed: 12147673]
  • Kamenetz F, Tomita T, Hsieh H, Seabrook G, Borchelt D, Iwatsubo T, Sisodia S, Malinow R. APP processing and synaptic function. Neuron. 2003;37:925–37. [PubMed: 12670422]
  • Kang J, Lemaire HG, Unterbeck A, Salbaum JM, Masters CL, Grzeschik KH, Multhaup G, Beyreuther K, Muller-Hill B. The precursor of Alzheimer's disease amyloid A4 protein resembles a cell-surface receptor. Nature. 1987;325:733–6. [PubMed: 2881207]
  • Ko YH, Hong S, Pedersen PL. Chemical mechanism of ATP synthase. Magnesium plays a pivotal role in formation of the transition state where ATP is synthesized from ADP and inorganic phosphate. J Biol Chem. 1999;274:28853–6. [PubMed: 10506126]
  • Kurochkin IV, Goto S. Alzheimer's beta-amyloid peptide specifically interacts with and is degraded by insulin degrading enzyme. FEBS Lett. 1994;345:33–7. [PubMed: 8194595]
  • Ladner CJ, Lee JM. Reduced high-affinity agonist binding at the M(1) muscarinic receptor in Alzheimer's disease brain: differential sensitivity to agonists and divalent cations. Exp Neurol. 1999;158:451–8. [PubMed: 10415152]
  • Lammich S, Kojro E, Postina R, Gilbert S, Pfeiffer R, Jasionowski M, Haass C, Fahrenholz F. Constitutive and regulated alpha-secretase cleavage of Alzheimer's amyloid precursor protein by a disintegrin metalloprotease. Proc Natl Acad Sci USA. 1999;96:3922–7. [PMC free article: PMC22396] [PubMed: 10097139]
  • Landfield PW, Morgan GA. Chronically elevating plasma Mg2+ improves hippocampal frequency potentiation and reversal learning in aged and young rats. Brain Res. 1984;322:167–71. [PubMed: 6097334]
  • LeBlanc AC, Koutroumanis M, Goodyer CG. Protein kinase C activation increases release of secreted amyloid precursor protein without decreasing Abeta production in human primary neuron cultures. J Neurosci. 1998;18:2907–13. [PubMed: 9526007]
  • Lee JY, Cole TB, Palmiter RD, Suh SW, Koh JY. Contribution by synaptic zinc to the gender-disparate plaque formation in human Swedish mutant APP transgenic mice. Proc Natl Acad Sci USA. 2002;99:7705–10. [PMC free article: PMC124328] [PubMed: 12032347]
  • Leissring MA, Farris W, Chang AY, Walsh DM, Wu X, Sun X, Frosch MP, Selkoe DJ. Enhanced proteolysis of beta-amyloid in APP transgenic mice prevents plaque formation, secondary pathology, and premature death. Neuron. 2003;40:1087–93. [PubMed: 14687544]
  • Lemke MR. Plasma magnesium decrease and altered calcium/magnesium ratio in severe dementia of the Alzheimer type. Biol Psychiatry. 1995;37:341–3. [PubMed: 7748988]
  • Lesne S, Ali C, Gabriel C, Croci N, MacKenzie ET, Glabe CG, Plotkine M, Marchand-Verrecchia C, Vivien D, Buisson A. NMDA receptor activation inhibits alpha-secretase and promotes neuronal amyloid-beta production. J Neurosci. 2005;25:9367–77. [PubMed: 16221845]
  • Lin JY, Chung SY, Lin MC, Cheng FC. Effects of magnesium sulfate on energy metabolites and glutamate in the cortex during focal cerebral ischemia and reperfusion in the gerbil monitored by a dual- probe microdialysis technique. Life Sci. 2002;71:803–11. [PubMed: 12074939]
  • Liu Y, Zhang YW, Wang X, Zhang H, You X, Liao FF, Xu H. Intracellular trafficking of presenilin 1 is regulated by beta-amyloid precursor protein and phospholipase D1. J Biol Chem. 2009;284:12145–52. [PMC free article: PMC2673283] [PubMed: 19276086]
  • Loeffler J, Huber G. Modulation of beta-amyloid precursor protein secretion in differentiated and nondifferentiated cells. Biochem Biophys Res Commun. 1993;195:97–103. [PubMed: 8395841]
  • Lovell MA, Robertson JD, Teesdale WJ, Campbell JL, Markesbery WR. Copper, iron and zinc in Alzheimer’s disease senile plaques. J Neurol Sci. 1998;158:47–52. [PubMed: 9667777]
  • Mantyh PW, Ghilardi JR, Rogers S, DeMaster E, Allen CJ, Stimson ER, Maggio JE. Aluminum, iron, and zinc ions promote aggregation of physiological concentrations of β-amyloid peptide. J Neurochem. 1993;61:1171–4. [PubMed: 8360682]
  • Marr RA, Guan H, Rockenstein E, Kindy M, Gage FH, Verma I, Masliah E, Hersh LB. Neprilysin regulates amyloid Beta peptide levels. J Mol Neurosci. 2004;22:5–11. [PubMed: 14742905]
  • Masters CL, Simms G, Weinman NA, Multhaup G, McDonald BL, Beyreuther K. Amyloid plaque core protein in Alzheimer disease and Down syndrome. Proc Natl Acad Sci USA. 1985;82:4245–9. [PMC free article: PMC397973] [PubMed: 3159021]
  • Matsuda H, Saigusa A, Irisawa H. Ohmic conductance through the inwardly rectifying K channel and blocking by internal Mg2+. Nature. 1987;325:156–9. [PubMed: 2433601]
  • Mattson MP, Cheng B, Culwell AR, Esch FS, Lieberburg I, Rydel RE. Evidence for excitoprotective and intraneuronal calcium-regulating roles for secreted forms of the beta-amyloid precursor protein. Neuron. 1993;10:243–54. [PubMed: 8094963]
  • Mayer ML, Westbrook GL, Guthrie PB. Voltage- dependent block by Mg2+ of NMDA responses in spinal cord neurones. Nature. 1984;309:261–3. [PubMed: 6325946]
  • Meziane H, Dodart JC, Mathis C, Little S, Clemens J, Paul SM, Ungerer A. Memory-enhancing effects of secreted forms of the beta-amyloid precursor protein in normal and amnestic mice. Proc Natl Acad Sci USA. 1998;95:12683–8. [PMC free article: PMC22891] [PubMed: 9770546]
  • Morimoto T, Ohsawa I, Takamura C, Ishiguro M, Kohsaka S. Involvement of amyloid precursor protein in functional synapse formation in cultured hippocampal neurons. J Neurosci Res. 1998;51:185–95. [PubMed: 9469572]
  • Mucke L, Abraham CR, Masliah E. Neurotrophic and neuroprotective effects of hAPP in transgenic mice. Ann N Y Acad Sci. 1996;777:82–8. [PubMed: 8624131]
  • Nowak L, Bregestovski P, Ascher P, Herbet A, Prochiantz A. Magnesium gates glutamate- activated channels in mouse central neurones. Nature. 1984;307:462–5. [PubMed: 6320006]
  • Oyanagi K. The nature of the parkinsonism- dementia complex and amyotrophic lateral sclerosis of Guam and magnesium deficiency. Parkinsonism and Related Disorders. 2005;11:S17–23. [PubMed: 15885623]
  • Oyanagi K, Kawakami E, Kikuchi-Horie K, Ohara K, Ogata K, Takahama S, Wada M, Kihira T, Yasui M. Magnesium deficiency over generations in rats with special references to the pathogenesis of the Parkinsonism-dementia complex and amyotrophic lateral sclerosis of Guam. Neuropathology. 2006;26:115–28. [PubMed: 16708544]
  • Phinney AL, Drisaldi B, Schmidt SD, Lugowski S, Coronado V, Liang Y, Horne P, Yang J, Sekoulidis J, Coomaraswamy J, Chishti MA, Cox DW, Mathews PM, Nixon RA, Carlson GA, St George-Hyslop P, Westaway D. In vivo reduction of amyloid-beta by a mutant copper transporter. Proc Natl Acad Sci USA. 2003;100:14193–8. [PMC free article: PMC283568] [PubMed: 14617772]
  • Prescott AR, Comerford JG, Magrath R, Lamb NJC, Warn RM. Effects of elevated intracellular magnesium on cytoskeletal integrity. J Cell Science. 1988;89:321–9. [PubMed: 3198695]
  • Price DL, Sisodia SS, Borchelt DR. Genetic neurodegenerative diseases: the human illness and transgenic models. Science. 1998;282:1079–83. [PubMed: 9804539]
  • Qi-Takahara Y, Morishima-Kawashima M, Tanimura Y, Dolios G, Hirotani N, Horikoshi Y, Kametani F, Maeda M, Saido TC, Wang R, Ihara Y. Longer forms of amyloid beta protein: implications for the mechanism of intramembrane cleavage by gamma-secretase. J Neurosci. 2005;25:436–45. [PubMed: 15647487]
  • Querfurth HW, Selkoe DJ. Calcium ionophore increases amyloid beta peptide production by cultured cells. Biochemistry. 1994;33:4550–61. [PubMed: 8161510]
  • Ray WJ, Yao M, Mumm J, Schroeter EH, Saftig P, Wolfe M, Selkoe DJ, Kopan R, Goate AM. Cell surface presenilin-1 participates in the gamma-secretase-like proteolysis of Notch. J Biol Chem. 1999;274:36801–7. [PubMed: 10593990]
  • Roher AE, Kasunic TC, Woods AS, Cotter RJ, Ball MJ, Fridman R. Proteolysis of A beta peptide from Alzheimer disease brain by gelatinase A. Biochem Biophys Res Commun. 1994;205:1755–61. [PubMed: 7811262]
  • Romani A, Marfella C, Scarpa A. Regulation of magnesium uptake and release in the heart and in isolated ventricular myocytes. Circ Res. 1993;72:1139–48. [PubMed: 8495544]
  • Romani A, Scarpa A. Regulation of cell magnesium. Arch Biochem Biophys 298:1-12. Romani AM, Scarpa A (2000) Regulation of cellular magnesium. Front Biosci. 1992;5:D720–34. [PubMed: 10922296]
  • Rossner S, Beck M, Stahl T, Mendla K, Schliebs R, Bigl V. Constitutive overactivation of protein kinase C in guinea pig brain increases alpha-secretory APP processing without decreasing beta-amyloid generation. Eur J Neurosci. 2000;12:3191–200. [PubMed: 10998103]
  • Schubert D, Behl C. The expression of amyloid beta protein precursor protects nerve cells from beta- amyloid and glutamate toxicity and alters their interaction with the extracellular matrix. Brain Res. 1993;629:275–82. [PubMed: 7906601]
  • Selkoe DJ. The molecular pathology of Alzheimer's disease. Neuron. 1991;6:487–98. [PubMed: 1673054]
  • Selkoe DJ. Translating cell biology into therapeutic advances in Alzheimer's disease. Nature. 1999;399:A23–31. [PubMed: 10392577]
  • Selkoe DJ. Alzheimer's disease: genes, proteins, and therapy. Physiol Rev. 2001a;81:741–66. [PubMed: 11274343]
  • Selkoe DJ. Clearing the brain's amyloid cobwebs. Neuron. 2001b;32:177–80. [PubMed: 11683988]
  • Selkoe DJ. Alzheimer's disease is a synaptic failure. Science. 2002;298:789–91. [PubMed: 12399581]
  • Seubert P, Oltersdorf T, Lee MG, Barbour R, Blomquist C, Davis DL, Bryant K, Fritz LC, Galasko D, Thal LJ. Secretion of beta-amyloid precursor protein cleaved at the amino terminus of the beta-amyloid peptide. Nature. 1993;361:260–63. [PubMed: 7678698]
  • Shcherbatykh I, Carpenter DO. The role of metals in the etiology of Alzheimer’s disease. J Alzheimers Dis. 2007;11:191–205. [PubMed: 17522444]
  • Shirotani K, Tsubuki S, Iwata N, Takaki Y, Harigaya W, Maruyama K, Kiryu-Seo S, Kiyama H, Iwata H, Tomita T, Iwatsubo T, Saido TC. Neprilysin degrades both amyloid beta peptides 1-40 and 1-42 most rapidly and efficiently among thiorphan- and phosphoramidon-sensitive endopeptidases. J Biol Chem. 2001;276:21895–901. [PubMed: 11278416]
  • Sinha S, Anderson JP, Barbour R, Basi GS, Caccavello R, Davis D, Doan M, Dovey HF, Frigon N, Hong J, Jacobson-Croak K, Jewett N, Keim P, Knops J, Lieberburg I, Power M, Tan H, Tatsuno G, Tung J, Schenk D, Seubert P, Suomensaari SM, Wang S, Walker D, Zhao J, McConlogue L, John V. Purification and cloning of amyloid precursor protein beta- secretase from human brain. Nature. 1999;402:537–40. [PubMed: 10591214]
  • Sisodia SS. Beta-amyloid precursor protein cleavage by a membrane-bound protease. Proc Natl Acad Sci USA. 1992;89:6075–9. [PMC free article: PMC49440] [PubMed: 1631093]
  • Skovronsky DM, Moore DB, Milla ME, Doms RW, Lee VM. Protein kinase C-dependent alpha- secretase competes with beta-secretase for cleavage of amyloid-beta precursor protein in the trans-golgi network. J Biol Chem. 2000;275:2568–75. [PubMed: 10644715]
  • Slutsky I, Abumaria N, Wu LJ, Huang C, Zhang L, Li B, Zhao X, Govindarajan A, Zhao MG, Zhuo M, Tonegawa S, Liu G. Enhancement of learning and memory by elevating brain magnesium. Neuron. 2010;65:165–77. [PubMed: 20152124]
  • Small DH, Nurcombe V, Reed G, Clarris H, Moir R, Beyreuther K, Masters CL. A heparin-binding domain in the amyloid protein precursor of Alzheimer's disease is involved in the regulation of neurite outgrowth. J Neurosci. 1994;14:2117–27. [PubMed: 8158260]
  • Sparks DL, Schreurs BG. Trace amounts of copper in water induce beta-amyloid plaques and learning deficits in a rabbit model of Alzheimer’s disease. Proc Natl Acad Sci USA. 2003;100:11065–9. [PMC free article: PMC196927] [PubMed: 12920183]
  • Subirana JA, Soler-Lopez M. Cations as hydrogen bond donors: a view of electrostatic interactions in DNA. Annu Rev Biophys Biomol Struct. 2003;32:27–45. [PubMed: 12598364]
  • Turner AJ, Fisk L, Nalivaeva NN. Targeting amyloid-degrading enzymes as therapeutic strategies in neurodegeneration. Ann N Y Acad Sci. 2004;1035:1–20. [PubMed: 15681797]
  • Vandenberg CA. Inward rectification of a potassium channel in cardiac ventricular cells depends on internal magnesium ions. Proc Natl Acad Sci USA. 1987;84:2560–4. [PMC free article: PMC304694] [PubMed: 2436236]
  • Vassar R, Bennett BD, Babu-Khan S, Kahn S, Mendiaz EA, Denis P, Teplow DB, Ross S, Amarante P, Loeloff R, Luo Y, Fisher S, Fuller J, Edenson S, Lile J, Jarosinski MA, Biere AL, Curran E, Burgess T, Louis JC, Collins F, Treanor J, Rogers G, Citron M. Beta-secretase cleavage of Alzheimer's amyloid precursor protein by the transmembrane aspartic protease BACE. Science. 1999;286:735–41. [PubMed: 10531052]
  • Vural H, Demirin H, Kara Y, Eren I, Delibas N. Alterations of plasma magnesium, copper, zinc, iron and selenium concentrations and some related erythrocyte antioxidant enzyme activities in patients with Alzheimer’s disease. J Trace Elements Med Biol. 2010;24:169–73. [PubMed: 20569929]
  • Wang DS, Dickson DW, Malter JS. Beta-Amyloid degradation and Alzheimer's disease. J Biomed Biotechnol. 2006;2006:58406. [PMC free article: PMC1559921] [PubMed: 17047308]
  • Wiltfang J, Esselmann H, Cupers P, Neumann M, Kretzschmar H, Beyermann M, Schleuder D, Jahn H, Ruther E, Kornhuber J, Annaert W, De SB, Saftig P. Elevation of beta-amyloid peptide 2-42 in sporadic and familial Alzheimer's disease and its generation in PS1 knockout cells. J Biol Chem. 2001;276:42645–57. [PubMed: 11526104]
  • Wolf FI, Torsello A, Fasanella S, Cittadini A. Cell physiology of magnesium. Mol Aspects Med. 2003;24:11–26. [PubMed: 12537986]
  • Xu X, Yang D, Wyss-Coray T, Yan J, Gan L, Sun Y, Mucke L. Wild-type but not Alzheimer-mutant amyloid precursor protein confers resistance against p53- mediated apoptosis. Proc Natl Acad Sci USA. 1999;96:7547–52. [PMC free article: PMC22123] [PubMed: 10377452]
  • Yamazaki T, Koo EH, Selkoe DJ. Trafficking of cell-surface amyloid beta-protein precursor. II. Endocytosis, recycling and lysosomal targeting detected by immunolocalization. J Cell Sci. 1996;109:999–1008. [PubMed: 8743947]
  • Yan R, Bienkowski MJ, Shuck ME, Miao H, Tory MC, Pauley AM, Brashier JR, Stratman NC, Mathews WR, Buhl AE, Carter DB, Tomasselli AG, Parodi LA, Heinrikson RL, Gurney ME. Membrane- anchored aspartyl protease with Alzheimer's disease beta-secretase activity. Nature. 1999;402:533–7. [PubMed: 10591213]
  • Yang LS, Ksiezak-Reding H. Ca2+ and Mg2+ selectively induce aggregates of PHF-tau but not normal human tau. J Neurosci Res. 1999;55:36–43. [PubMed: 9890432]
  • Yu J, Sun M, Chen Z, Lu J, Liu Y, Zhou L, Xu X, Fan D, Chui D. Magnesium modulates amyloid-beta protein precursor trafficking and processing. J Alzheimers Dis. 2010;20:1091–106. [PubMed: 20413885]
  • Zhao J, Wang WN, Tan YC, Zheng Y, Wang ZX. Effect of Mg(2+) on the kinetics of guanine nucleotide binding and hydrolysis by Cdc42. Biochem Biophys Res Commun. 2002;297:653–8. [PubMed: 12270144]
*

Dehua Chui, Z. Chen and J. Yu contributed equally to this work.

© 2011 The Authors.

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