Medical Hypotheses 85 (2015) 219–223

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Medical Hypotheses

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Glucose-6-phosphate dehydrogenase deficiency and Alzheimer’sdisease: Partners in crime? The hypothesis

http://dx.doi.org/10.1016/j.mehy.2015.05.0060306-9877/� 2015 Elsevier Ltd. All rights reserved.

⇑ Tel.: +90 (212) 338 11 60, mobile: +90 (533) 4179369; fax: +90 (212) 338 11 68.E-mail address: nulusu@ku.edu.tr

N. Nuray Ulusu ⇑Koç University, School of Medicine, Rumelifeneri Yolu, Sarıyer, Istanbul, Turkey

a r t i c l e i n f o a b s t r a c t

Article history:Received 30 January 2015Accepted 5 May 2015

Alzheimer’s disease is a multifaceted brain disorder which involves various coupled irreversible, progres-sive biochemical reactions that significantly reduce quality of life as well as the actual life expectancy.Aging, genetic predispositions, head trauma, diabetes, cardiovascular disease, deficiencies in insulin sig-naling, dysfunction of mitochondria-associated membranes, cerebrovascular changes, high cholesterollevel, increased oxidative stress and free radical formation, DNA damage, disturbed energy metabolism,and synaptic dysfunction, high blood pressure, obesity, dietary habits, exercise, social engagement, andmental stress are noted among the risk factors of this disease.

In this hypothesis review I would like to draw the attention on glucose-6-phosphate dehydrogenasedeficiency and its relationship with Alzheimer’s disease. This enzymopathy is the most common humancongenital defect of metabolism and defined by decrease in NADPH+H+ and reduced form of glutathioneconcentration and that might in turn, amplify oxidative stress due to essentiality of the enzyme. Thismost common enzymopathy may manifest itself in severe forms, however most of the individuals withthis deficiency are not essentially symptomatic. To understand the sporadic Alzheimer’s disease, thewriter of this paper thinks that, looking into a crystal ball might not yield much of a benefit butglucose-6-phosphate dehydrogenase deficiency could effortlessly give some clues.

� 2015 Elsevier Ltd. All rights reserved.

Introduction

Alzheimer’s disease (AD) is a multi-factorial progressive pro-teopathy. This protein misfolding disease has five commonlyobserved features: cortical atrophy, neuron degeneration, neuronalloss, accumulation of extracellular (amyloid b containing) plaquesand accumulation of intracellular (tau) neurofibrillary tangles. Inthe occurrence of tangles and senile plaques, oxidative stress hasa triggering effect in emergence of disease related pathologies[1–5]. Amyloid b (Ab) plaques and tangles are hallmarks ofAlzheimer’s disease [6]. Tau phosphorylation is a key factor in dis-ease progression [7]. Mutations on chromosome 21 are found to beinvolved for the formation of familial Alzheimer’s disease, beforethe age of 65 [8]. Most cases of AD occur ‘sporadic’ and othersare associated with inheritance of one or more alleles such asapolipoprotein E e4 or with mutations in the genes, which areamyloid precursor protein, presenilin-1, presenilin-2, or expressionof triggering receptor on myeloid cells 2 gene, that are stronglyassociated with late-onset of Alzheimer’s disease [9,10]. The detailsof the sporadic AD are not fully understood and the underlying

preliminary etiologies of AD still remain elusive and open to muchdebate. However, aging, diabetes, malfunctioning insulin signaling,dysfunction of mitochondria-associated membranes, cerebrovas-cular changes, increased oxidative stress and free radical forma-tion, DNA damage, disturbed energy metabolism, and synapticdysfunction are among risk factors for sporadic AD. Glucose6-phosphate dehydrogenase deficiency (G6PD) may be one of theleading reasons of the sporadic AD because G6PD enzymes’ sub-strate NADPH+H+ has very important protective roles in oxidativestress [11–21]. In fact, it has also been proposed that the mitochon-drial failure and the related oxidative stress seem to precede amy-loid deposition and, consequently, the emergence of the actualneurodegeneration [22]. G6PD enzyme can combat with oxidativestress by the aid of glutathione reductase; consequently it relies onthe activity of a series of enzymes, such as 6-phoshogluconatedehydrogenase, glutathione reductase, glutathione-S-transferase,glutathione peroxidase, and catalase. G6PD deficiency is definedby the decrease in NADPH+H+ and reduced form of glutathioneconcentrations. If the G6PD enzyme activity decreases, strictly inline with that, reduced form of nicotinamide adenine dinucleotidephosphate will also diminish and finally cell/cells cannot ‘reduce’oxidized glutathione to it is reduced form and thus cannot combatwith the degenerative effects of oxidative stress. Cells with normal

220 N.N. Ulusu / Medical Hypotheses 85 (2015) 219–223

G6PD enzyme activity can reduce oxidized NADP+ to its reducedstate, NADPH++H+ is essential for the maintenance of the reducedglutathione pool as it provides the reducing equivalents for biosyn-thetic reactions and the oxidation–reduction involved in protec-tion against the toxicity of reactive oxygen species (ROS) andallowing the regeneration of GSH (reduced glutathione).Theoretically, any metabolic change that alters NADPH+H+ concen-tration negatively will also lower cellular defense against oxidativestress. Furthermore, these alterations in the activities of the antiox-idant enzymes are accompanied by significant changes in oxidativestress; consequently, oxidative stress might be responsible for thedevelopment of various cellular complications [16,17,19,21,23].

The studies on AD demonstrated that, 4 kDa amyloid b proteins[Ab] trigger a toxic cascade that induces microtubule-associatedprotein s (MAPT) hyperphosphorylation [24,25]. It has been knownthat mitochondrial failure and oxidative stress have enormouseffects on neurodegenerative processes [22].

Mitochondria have a key role between life and death and thisrole is investigated in various pathologies from cardiovascular toneurological diseases. Life and death are balanced on the Ca2+

homeostasis and reactive oxygen radicals’ concentrations in manycases, which are induced by mitochondrial failure [26]. It is estab-lished that cytosolic phospholipase A2a activity plays a decisiverole in the apoptotic neuronal death and caspases-3 andcaspases-8 have inevitable roles in the whole process [27]. In theemergence and/or progress of the disease, accumulation ofamyloid-b peptide [Ab], due to overproduction and/or failure ofclearance mechanisms are very decisive. Ab self-aggregates intooligomers, which can be of various sizes, since senile plaques areincreasing in number, densities and size by aging [28]. Crudelyfor AD, we may say that the disease begins with the classic amyloidprotein plaques and neurofibrillary tangles, and followed by thegradual emergence of symptoms such as dementia and memoryloss, which will eventually conclude with death [29].

Novel targets for Alzheimer’s disease

Amyloid-b peptides are the primary causative agents of AD.However, the studies show us that it is not the sole factor in AD eti-ology. Amyloid independent factors, such as AD-related genes,defective endo-lysosomal trafficking, altered intracellular signalingcascades, in addition to impaired neurotransmitter are also impor-tant factors that have key roles in the development of disease [30].The cyclin-dependent kinase (Cdk5) and glycogen synthase kinaseGSK3b have been shown to be involved in anomalous tau phospho-rylation. Both of these enzymes are protein kinases. The Cdk5 playsa critical role in brain development and is related with neurogen-esis. Deregulation of this protein kinase, as induced by extracellu-lar amyloid loading, results in tau hyperphosphorylations, and thustriggering a sequence of molecular events that lead to neuronaldegeneration. Inhibitors of Cdk5 and GSK3b and antisense oligonu-cleotides exert protection against neuronal death [31]. Inhibition ofGSK-3 reverses AD pathogenesis via restoration of lysosomal acid-ification and reactivation of mTOR. This enzyme regulates lysoso-mal acidification [32,33]. Glycogen synthase kinase-3 (GSK-3)also has key roles in the regulation of glucose metabolism.Acetylcholinesterase, butyrylcholinesterase, beta secretase are alsoinvolved in AD [34]. b-Secretase has therapeutic potential for ADbecause this enzyme has rate limiting function in production ofthe amyloid b peptide. Amyloid-b precursor protein (APP) enzymeis an allosteric membrane-anchored pepsin-like aspartic proteasethat cleaves the amyloid precursor. For these reasons, b-secretaseand APP-cleaving enzymes have preventive and therapeutic prop-erties in this life-threatening disease [35,36]. One of the novel find-ings on AD is that, APP is processed by a-secretase, b-secretase,theta-secretase, and c-secretase enzymes and the

non-amyloidogenic Glu11 site being the major b-secretase cleav-age site of BACE1 [37]. It has been established that c-secretaseinhibitors lead to accumulation of amyloid precursor [38].Another enzyme that participates in AD is human tau-proteinkinase I. This enzyme is serine/threonine protein kinase and knownas glycogen synthase [39]. Neprilysin is a zinc dependentmetallo-endopeptidase and has a function on misfolding proteins.This enzyme degrades Ab peptides and through this marvelousfunction, this enzyme slows the progression of AD and hence itsactivity can be induced by drugs [40]. On the other hand, phospho-diesterase type 5 (PDE5) mediates the degradation of cGMP and,PDE5 inhibitors might possibly prevent or delay AD [41]. It hasbeen investigated that thiamine and thiamine-dependent enzymessuch as transketolase, apolipoprotein E, alpha-I-antitrypsin,pyruvate dehydrogenase complex, p53, and glycogen synthasekinase-3 beta activities are decreased in brain and peripheraltissues of patients with AD [43]. Beside thiamine, vitaminD3-enriched diet has been shown to improve beneficial effect inpatients with AD [5,42].

Effect of glucose 6-phosphate dehydrogenase deficiency onsporadic Alzheimer’s disease

Aging is a very multifarious process, that involves interplaybetween different metabolic pathways yet there are some leadingfactors such as oxidative stress which increases in an agingbrain [43]. It has been also investigated that,trans-4-hydroxy-2-nonenal, a product of lipid peroxidation, formsconjugates with a variety of nucleophilic groups such as thiolsor amino moieties. These lipid peroxidation products(trans-4-hydroxy-2-nonenal) leading to glutathione conjugatesare detected in the human brain [44]. Aging (senescence) increasesthe susceptibility to age-related diseases. It has been widely estab-lished that, elderly-populations have an increased predisposition tostroke, Alzheimer’s disease, Parkinson’s disease, dementia, cardio-vascular disease, cancer, arthritis, cataract, osteoporosis, diabetesand hypertension. Accumulation of genetic instability, togetherwith the disturbed balance of redox state in metabolic pathwaysmight be the underlying cause behind this vulnerability. G6PD defi-ciency is a triggering factor in oxidative stress mechanism which inturn, exacerbates the consequent lipid peroxidation [45].Researchers have been trying to identify factors that increase therisk of AD such as aerobic exercise, pesticides, elevated serumcholesterol concentrations, carotenoids, abdominal obesity, andexposure to aluminum, head injury, malnutrition, immune systemdysfunctions, and infectious agents [46–51]. G6PD deficiency isthe most common genetic defect and enzymopathy worldwide,affecting approximately 400 million people and causing acutehemolysis in patients exposed to oxidative compounds such asmenthol, naphthalene, antimalarial drugs, and fava beans [52].G6PD is the first and the rate-limiting enzyme of the pentose phos-phate pathway (PPP). G6PD produces cellular NADPH, which isrequired for the many biosynthetic steps of fatty acids and choles-terol, lipogenesis for short, energy homeostasis, glucose metabolismand essential for detoxification reactions of the free radicals [11,53].On the other hand, molecules that are synthesized in PPP are essen-tial for various biosynthetic reactions as well, and their synthesesare regulated according to the physiological needs of cells.

Free radicals might be induced in several ways however the piv-otal point of that does not reside in the production of free radicalsbut how they are handled by the organism, or removed. These rad-icals can be removed by series of reactions. Most of the detoxifica-tion reactions accomplished by linked NADP: NADPH to theglutathione redox couple (GSSG: GSH) system which participatesin diverse biological processes [54]. AD is the outcome of complex

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interactions among several factors which are not fully understoodyet; nevertheless, it is clear that oxidative stress and inflammatorypathways are among these factors [55]. In G6PD deficiency, home-ostasis is not maintained therefore cells lose their ability to carryout their normal functions and the detoxification reactions cannotbe sustained properly. Cells are left vulnerable to the toxic effectsof the free radicals in the failure of coupled redox system [56]. Ifa patient has a mild G6PD deficiency, this deficiency will translateinto the insufficient radical detoxification. And failure in detoxifi-cation system will cause cellular oxidative damage. In the failureof the detoxification system, free radical, toxins will not be detox-ified which makes the organism vulnerable to the harmful effects.These radicals will lead to aging, and age-related diseases such ascardiovascular disease, cancer, neurodegenerative disorders, andother chronic conditions [57]. It is known that major risk factorof AD is aging and also, accordingly, oxidative damage might bethe earliest event in AD onset [58,59]. In addition to thisfree-radical production, the associated alterations in vasoregula-tion induced NADPH oxidase, which is an important link betweenAb and cerebrovascular dysfunction, may be the underlying causeof the alteration in cerebral blood flow regulation observed in AD[60]. It is known that oxidative stress has a crucial role in neuronalcell death. In fact, the neuronal cell death is closely associatedwith neurodegenerative disorders such as Alzheimer’s disease,Parkinson’s disease, as well as brain stroke/ischemia and traumaticbrain injury [61]. NADPH+H+ is essential for NADPH oxidase, cyto-chrome p450 system [62]. On the other hand, one of the most strik-ing finding of AD is the cholesterol binding ability of the amyloidprecursor protein [63]. And G6PD is directly involved in importantroles in lipid peroxidation and lipid metabolism and detoxificationof radicals [12,17,64,65].

In our earlier studies, we have also found that administrationof vitamin E in combination with other antioxidants such asstobadine and vitamin C, prevents both diabetes- andgalactosemia-induced elevations in oxidative stress, and protectsmyocardial and retinal Na+, K+-ATPase and Ca2+-ATPases againstoxidative damage [66,67]. In our previous study, we have foundthat there is a direct correlation between aging and G6PD enzymekinetic behavior and finally with the AD. Aging have harmfuleffects on G6PD; it could even change the kinetic mechanism ofthe enzyme [12].

We know that oxidative stress is increased in G6PD deficiency,since the reduced form of NADP+ is decreased and insufficientNADPH+H+ supply of reduced glutathione in the cells, that is usedfor free radical detoxification. Moreover, NADPH+H+ is also used byNADPH-oxidase enzyme. The NADPH oxidase family of superoxideand hydrogen peroxide producing proteins has emerged as animportant source of reactive oxygen species in signal transduction[68]. NADPH oxidase is a unique, multi-protein, electron transportsystem that produces large amounts of superoxide via the reduc-tion of molecular oxygen. Reactive oxygen species of NADPH des-cent are known to be involved in a variety of physiologicalprocesses, including its involvement in immune regulation and sig-nal transduction. The involvement of NADPH oxidase in neurode-generation and Alzheimer disease is also an established one [69].Finally, NADPH+H+ contributed to lipid anabolic pathways as well.So briefly, it can be said that G6PD deficiency on Alzheimer’s dis-ease is need to be examined in many ways. It has been discoveredthat phosphatidylcholine molecules are significantly diminished inAlzheimer’s Disease [50,70,71].

Oxidative stress dependent Alzheimer’s disease

In a previous heterozygous G6PD deficient mice study research-ers established the correlation between accumulations of reactive

oxygen species that are associated with oxidative damage toDNA in specific areas of the brain with aging. Researchers con-cluded that the increased levels of oxidative DNA damage in differ-ent brain regions, in addition to cell types that were commonlyassociated with pathological changes such as loss of Purkinje cells,increased neuronal nuclear diameter, increased vacuolation andincreased prevalence of chromatolytic neurons [72]. The morpho-logical and morphometric estimation of the dendrites and the den-dritic spines of the Purkinje cells from the inferior surface of thecerebellar hemispheres in Alzheimer’s disease brains revealed sub-stantial alterations of the dendritic arborization and marked loss ofthe dendritic spines, which may be related to cognitive impairmentand motor deficits in Alzheimer’s disease [73].

The complex pathogenesis of AD involves multiple contributingfactors, including amyloid beta peptide accumulation, inflamma-tion and oxidative stress [74]. To this end, redox biochemistry isone of the most important key dynamic of cell biology which iscoming to be appreciated for paramount significance in the AD[75]. Endoplasmic reticulum stress (ER stress) is associated withinflammation that could act as a potential event involved in ADdevelopment [76]. It has been demonstrated that the depletion ofNADPH in the ER lumen sensitizes the cells towards oxidative inju-ries and suggests that autophagy is involved in the consequent celldeath [77]. Hexose-6-phosphate dehydrogenase (H6PDH) is a lumi-nal enzyme and able to catalyze the first two reactions of pentosephosphate pathway inside the endoplasmic reticulum (ER) thatgenerates NADPH for ER enzymes It has been also demonstratedthat the maintenance of the proper NADPH/NADP+ ratio in the ERlumen has a survival value in a variety of cell types [78]. H6PDHhas emerged as an important factor in setting the redox status ofthe ER lumen. H6PDH knockout mice have also offered an insightinto muscle physiology as they also present with a severe vacuolat-ing myopathy, abnormalities of glucose homeostasis and activationof the unfolded protein response due to ER stress, and a number ofmechanisms driving this phenotype are thought to be involved[79]. This enzyme is distinct from cytosolic G6PD by several fea-tures but have similar functions such as localization and separatepyridine nucleotide pools plus H6PD provides NADPH for luminalreductases [80]. Accumulating evidence has shown that oxidativestress-induced damage may play an important role in the initiationand progression of AD pathogenesis. Redox impairment occurswhen there is an imbalance between the production and quenchingof free radicals from oxygen species. These reactive oxygen speciesaugment the formation and aggregation of amyloid-b and tau pro-tein hyperphosphorylation and vice versa [81].

The present hypothesis asserts that the involvement of theG6PD enzyme deficiency may have a key additive role inPurkinje cells loss, as well as loss of dendritic spines and neurofib-rillary degeneration in Alzheimer’s disease neuropathology. As aresult, there are a number of persisting questions that require fur-ther clarification.

Conclusion

It is very hard to answer why Alzheimer’s develops in somepeople and not in others. Perhaps, the most important, triggeringfactor is the accumulation of free radicals, in other words oxidativestress, following to the hereditary factors in AD. There have beensignificant number of studies on the interplay between AD, agingand oxidative stress. The amount of free radical production mustbe balanced by the involvement of vitamins, antioxidant mole-cules, glutathione and radical detoxifying enzymes. Virtually everymetabolic alteration which disturbs this balance will lead to unde-sired consequences, first in cellular level, then in tissue level, andeventually, affecting the whole organism.

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Further research, based on the current findings in G6PD and theAlzheimer’s disease might have very potent and striking effects onthe understanding of AD. Accumulating literature is indicatingthat, one of the main causes of sporadic AD might be the G6PDdeficiency.

To establish an accurate correlation between AD and G6PD defi-ciency, it is advisable that, each patient with AD should bescreened.

Conflict of interest

There is no conflict of interest with any company.

References

[1] Sambamurti K, Greig NH, Utsuki T, Barnwell EL, Sharma E, Mazell C, et al.Targets for AD treatment: conflicting messages from c-secretase inhibitors. JNeurochem 2011;117:359–74.

[2] Fändrich M, Schmidt M, Grigorieff N. Recent progress in understandingAlzheimer’s b-amyloid structures. Trends Biochem Sci 2011;36:338–45.

[3] Yu QS, Reale M, Kamal MA, Holloway HW, Luo W, Sambamurti K, et al.Synthesis of the Alzheimer drug Posiphen into its primary metabolic products[+]-N1-norPosiphen, [+]-N8-norPosiphen and [+]-N1, N8-bisnorPosiphen, theirinhibition of amyloid precursor protein, a-Synuclein synthesis, interleukin-1brelease, and cholinergic action. Antiinflamm Antiallergy Agents Med Chem2013;12:117–28.

[4] Shin RW, Ogomori K, Kitamoto T, Tateishi J. Increased tau accumulation insenile plaques as a hallmark in Alzheimer’s disease. Am J Pathol1989;134:1365–71.

[5] Yu J, Gattoni-Celli M, Zhu H, Bhat NR, Sambamurti K, Gattoni-Celli S, et al.Vitamin D3-enriched diet correlates with a decrease of amyloid plaques in thebrain of AbPP transgenic mice. J Alzheimers Dis 2011;25:295–307.

[6] Blennow K, de Leon MJ, Zetterberg H. Alzheimer’s disease. Lancet 2006;368:387–403.

[7] Noble W, Pooler AM, Hanger DP. Advances in tau-based drug discovery. ExpertOpin Drug Discov 2011;6:797–810.

[8] Goate A, Chartier-Harlin MC, Mullan M, Brown J, Crawford F, Fidani L, et al.Segregation of a missense mutation in the amyloid precursor protein genewith familial Alzheimer’s disease. Nature 1991;349:704–6.

[9] Ryan NS, Rossor MN. Correlating familial Alzheimer’s disease gene mutationswith clinical phenotype. Biomark Med 2010;1:99–112.

[10] Miyoshi K. What is ‘early onset dementia’? Psychogeriatrics 2009;9:67–72.[11] Jiyoung P, Ho Kyung R, Kang Ho K, Sung Sik C, Yun Sok L, Jae Bum K.

Overexpression of glucose-6-phosphate dehydrogenase is associated withlipid dysregulation and insulin resistance in obesity. Mol Cell Biol2005;25:5146–57.

[12] Ulusu NN, Tandogan B. Purification and kinetics of sheep kidney cortexglucose-6-phosphate dehydrogenase. Comp Biochem Physiol B Biochem MolBiol 2006;143:249–55.

[13] Cheung CY, Ong YT, Ikram MK, Ong SY, Li X, Hilal S, et al. Microvascularnetwork alterations in the retina of patients with Alzheimer’s disease.Alzheimers Dement 2014;10:135–42.

[14] Dogru Pekiner B, Das� Evcimen N, Ulusu NN, Bali M, Karasu C. Effects of vitaminE on microsomal Ca[2+]-ATPase activity and calcium levels in streptozotocin-induced diabetic rat kidney. Cell Biochem Funct 2003;21:177–82.

[15] Das Evcimen N, Ulusu NN, Karasu C, Dogru B. Adenosine triphosphataseactivity of streptozotocin-induced diabetic rat brain microsomes. Effect ofvitamin E. Gen Physiol Biophys 2004;23:347–55.

[16] Ulusu NN, Turan B. Beneficial effects of selenium on some enzymes of diabeticrat heart. Biol Trace Elem Res 2005;103:207–16.

[17] Can B, Ulusu NN, Kilinç K, Leyla Acan N, Saran Y, Turan B. Selenium treatmentprotects diabetes-induced biochemical and ultrastructural alterations in livertissue. Biol Trace Elem Res 2005;105:135–50.

[18] Tuncay E, Seymen AA, Tanriverdi E, Yaras N, Tandogan B, Ulusu NN, et al.Gender related differential effects of omega-3E treatment on diabetes-inducedleft ventricular dysfunction. Mol Cell Biochem 2007;304:255–63.

[19] Ozdemir S, Tandogan B, Ulusu NN, Turan B. Angiotensin II receptor blockageprevents diabetes-induced oxidative damage in rat heart. Folia Biol [Praha]2009;55:11–6.

[20] Pekiner B, Ulusu NN, Das-Evcimen N, Sahilli M, Aktan F, Stefek M, et al. In vivotreatment with stobadine prevents lipid peroxidation, protein glycation andcalcium overload but does not ameliorate Ca2+-ATPase activity in heart andliver of streptozotocin-diabetic rats: comparison with vitamin E. Antioxidantsin Diabetes-Induced Complications Study Group. Biochim Biophys Acta2002;1588:71–8.

[21] Ulusu NN, Sahilli M, Avci A, Canbolat O, Ozansoy G, Ari N, et al. Pentosephosphate pathway, glutathione-dependent enzymes and antioxidant defenseduring oxidative stress in diabetic rodent brain and peripheral organs: effectsof stobadine and vitamin E. Neurochem Res 2003;28:815–23.

[22] Selvatici R, Marani L, Marino S, Siniscalchi A. In vitro mitochondrial failure andoxidative stress mimic biochemical features of Alzheimer disease. NeurochemInt 2013;63:112–20.

[23] Tandogan B, Ulusu NN. Comparative in vitro effects of some metal ions onbovine kidney cortex glutathione reductase. Prep Biochem Biotechnol2010;40:405–11.

[24] Maloney B, Sambamurti K, Zawia N, Lahiri DK. Applying epigenetics toAlzheimer’s disease via the latent early-life associated regulation [LEARn]model. Curr Alzheimer Res 2012;9:589–99.

[25] Katzman R. Alzheimer’s disease. N Engl J Med 1986;314:964–73.[26] Sochocka M, Koutsouraki ES, Gasiorowski K, Leszek J. Vascular oxidative

stress and mitochondrial failure in the pathobiology of Alzheimer’s disease: anew approach to therapy. CNS Neurol Disord Drug Targets 2013;12:870–81.

[27] Sagy-Bross C, Hadad N, Levy R. Cytosolic phospholipase A2a upregulationmediates apoptotic neuronal death induced by aggregated amyloid-b peptide1–42. Neurochem Int 2013;63:541–50.

[28] Berg L, McKeel Jr DW, Miller JP, Storandt M, Rubin EH, Morris JC, et al.Clinicopathologic studies in cognitively healthy aging and Alzheimer’s disease:relation of histologic markers to dementia severity, age, sex, andapolipoprotein E genotype. Arch Neurol 1998;55:326–35.

[29] Selkoe DJ. Alzheimer disease: mechanistic understanding predicts noveltherapies. Ann Intern Med 2004;140:627–38.

[30] Pimplikar SW, Nixon RA, Robakis NK, Shen J, Tsai LH. Amyloid-independentmechanisms in Alzheimer’s disease pathogenesis. J Neurosci2010;10:14946–54.

[31] Maccioni RB, Muñoz JP, Barbeito L. The molecular bases of Alzheimer’s diseaseand other neurodegenerative disorders. Arch Med Res 2001;32:367–81.

[32] Avrahami L, Farfara D, Shaham-Kol M, Vassar R, Frenkel D, Eldar-Finkelman H.Inhibition of glycogen synthase kinase-3 ameliorates b-amyloid pathology andrestores lysosomal acidification and mammalian target of rapamycin activityin the Alzheimer disease mouse model: in vivo and in vitro studies. J Biol Chem2013;288:1295–306.

[33] Medina M, Avila J. New insights into the role of glycogen synthase kinase-3 inAlzheimer’s disease. Expert Opin Ther Targets 2014;18:69–77.

[34] Anand P, Singh B. Flavonoids as lead compounds modulating the enzymetargets in Alzheimer’s disease. Med Chem Res 2013;22:3061–75.

[35] Wang W, Liu Y, Lazarus RA. Allosteric inhibition of BACE1 by an exosite-binding antibody. Curr Opin Struct Biol 2013;23:797–805.

[36] Tan J, Evin G. b-Site APP-cleaving enzyme 1 trafficking and Alzheimer’s diseasepathogenesis. J Neurochem 2012;120:869–80.

[37] Deng Y, Wang Z, Wang R, Zhang X, Zhang S, Wu Y, et al. Amyloid-b protein [Ab]Glu11 is the major b-secretase site of b-site amyloid-b precursor protein-cleaving enzyme 1[BACE1], and shifting the cleavage site to Ab Asp1contributes to Alzheimer pathogenesis. Eur J Neurosci 2013;37:1962–9.

[38] Sambamurti K, Greig NH, Utsuki T, Barnwell EL, Sharma E, Mazell C, et al.Targets for AD treatment: conflicting messages from c-secretase inhibitors.Neurochemistry 2011;117:359–74.

[39] Aoki M, Yokota T, Sugiura I, Sasaki C, Hasegawa T, Okumura C, et al. Structuralinsight into nucleotide recognition in tau-protein kinase I/glycogen synthasekinase 3 beta. Acta Crystallogr D Biol Crystallogr 2004;60:439–46.

[40] El-Amouri SS, Zhu H, Yu J, Marr R, Verma IM, Kindy MS. Neprilysin: an enzymecandidate to slow the progression of Alzheimer’s disease. Am J Pathol2008;172:1342–54.

[41] Fiorito J, Saeed F, Zhang H, Staniszewski A, Feng Y, Francis YI, et al. Synthesis ofquinoline derivatives: discovery of a potent and selective phosphodiesterase 5inhibitor for the treatment of Alzheimer’s disease. Eur J Med Chem2013;60:285–94.

[42] Kv Lu’o’ng, Nguyen LT. Role of thiamine in Alzheimer’s disease. Am JAlzheimers Dis Other Demen 2011;26:588–98.

[43] Floyd RA, Hensley K. Oxidative stress in brain aging. Implications fortherapeutics of neurodegenerative diseases. Neurobiol Aging 2002;23:795–807.

[44] Völkel W, Sicilia T, Pähler A, Gsell W, Tatschner T, Jellinger K, et al. Increasedbrain levels of 4-hydroxy-2-nonenal glutathione conjugates in severeAlzheimer’s disease. Neurochem Intern 2006;48:679–86.

[45] Ondei LS, Silveira LM, Leite AA, Souza DR, Pinhel MA, Percário S, et al. Lipidperoxidation and antioxidant capacity of G6PD-deficient patients with A-[202G>A] mutation. Genet Mol Res 2009;10:1345–51.

[46] Vidoni ED, Van Sciver A, Johnson DK, He J, Honea R, Haines B, et al. Acommunity-based approach to trials of aerobic exercise in aging andAlzheimer’s disease. Contemp Clin Trials 2012;33:1105–16.

[47] Richardson JR, Roy A, Shalat SL, von Stein RT, Hossain MM, Buckley B, et al.Elevated serum pesticide levels and risk for Alzheimer disease. JAMA Neurol2014;71:284–90.

[48] Dias IH, Polidori MC, Li L, Weber D, Stahl W, Nelles G, et al. Plasma levels ofHDL and carotenoids are lower in dementia patients with vascularcomorbidities. J Alzheimers Dis 2014;40:399–408.

[49] Camargos EF, Louzada FM, Nóbrega OT. Wrist actigraphy for measuring sleepin intervention studies with Alzheimer’s disease patients: application,usefulness, and challenges. Sleep Med Rev 2013;17:475–88.

[50] Debette S, Wolf C, Lambert JC, Crivello F, Soumaré A, Zhu YC, et al. Abdominalobesity and lower gray matter volume: a Mendelian randomization study.Neurobiol Aging 2014;35:378–86.

[51] Armstrong RA. What causes Alzheimer’s disease? Folia Neuropathol2013;51:169–88.

N.N. Ulusu / Medical Hypotheses 85 (2015) 219–223 223

[52] Patrinostro X, Carter ML, Kramer AC, Lund TC. A model of glucose-6-phosphatedehydrogenase deficiency in the zebrafish. Exp Hematol 2013;41:697–710.

[53] Berg JM, Tymoczko JL, Stryer L. Biochemistry. United States of America: W.H.Freeman and Company; 2002.

[54] Xie HB, Cammarato A, Rajasekaran NS, Zhang H, Suggs JA, Lin HC, et al. TheNADPH metabolic network regulates human aB-crystallin cardiomyopathyand reductive stress in Drosophila melanogaster. PLoS Genet 2013;9:1–14.

[55] Scotti L, Mendonca FJB, da Silva MS, Pitta IR, Scotti MT. Biochemical changesevidenced in Alzheimer’s disease: a mini-review. Lett Drug Des Discov2014;11:240–8.

[56] Russell RL, Siedlak SL, Raina AK, Bautista JM, Smith MA, Perry G. Increasedneuronal glucose-6-phosphate dehydrogenase and sulfhydryl levels indicatereductive compensation to oxidative stress in Alzheimer disease. ArchBiochem Biophys 1999;370:236–9.

[57] Rahman K. Studies on free radicals, antioxidants, and co-factors. Clin IntervAging 2007;2:219–36.

[58] Wirz KTS, Keitel S, Swaab DF, Verhaagen J, Bossers K. Early molecular changesin Alzheimer disease: can we catch the disease in its presymptomatic phase? JAlzheimers Dis 2014;38:719–40 [Review].

[59] Nunomura A, Perry G, Aliev G, Hirai K, Takeda A, Balraj EK, et al. Oxidativedamage is the earliest event in Alzheimer disease. J Neuropathol Exp Neurol2001;60:759–67.

[60] Park L, Anrather J, Zhou P, Frys K, Pitstick R, Younkin S, et al. NADPH-oxidase-derived reactive oxygen species mediate the cerebrovascular dysfunctioninduced by the amyloid beta peptide. J Neurosci 2005;16:1769–77.

[61] Navarro-Yepes J, Zavala-Flores L, Anandhan A, Wang F, Skotak M, Chandra N,et al. Antioxidant gene therapy against neuronal cell death. Pharmacol Ther2014;142:206–30.

[62] Stanton RC. Glucose-6-phosphate dehydrogenase, NADPH, and cell survival.IUBMB Life 2012;64:362–9.

[63] Song YL, Kenworthy AK, Sanders CR. Cholesterol as a co-solvent and a ligandfor membrane proteins. Protein Sci 2014;23:1–22.

[64] Schwartz AG, Pashko LL. Dehydroepiandrosterone, glucose-6-phosphatedehydrogenase, and longevity. Ageing Res Rev 2004;3:171–87.

[65] Guz G, Demirogullari B, Ulusu NN, Dogu C, Demirtola A, Kavutcu M, et al.Stobadine protects rat kidney against ischaemia/reperfusion injury. Clin ExpPharmacol Physiol 2007;34:210–6.

[66] Dogru Pekiner B, Das� Evcimen N, Ulusu NN, Bali M, Karasu C. Effects of vitaminE on microsomal Ca[2+]-ATPase activity and calcium levels in streptozotocin-induced diabetic rat kidney. Cell Biochem Funct 2003;21:177–82.

[67] Pekiner B, Ulusu NN, Das-Evcimen N, Sahilli M, Aktan F, Stefek M, et al. In vivotreatment with stobadine prevents lipid peroxidation, protein glycation and

calcium overload but does not ameliorate Ca2+-ATPase activity in heart andliver of streptozotocin-diabetic rats: comparison with vitamin E. BiochimBiophys Acta 2002;9:71–8.

[68] Demirer S, Ulusu NN, Aslim B, Kepenekci I, Ulusoy C, Andrieu MN, et al.Protective effects of Lactobacillus delbrueckii subsp. bulgaricus B3 on intestinalenzyme activities after abdominal irradiation in rats. Nutr Res 2007;27:300–5.

[69] Brown DI, Griendling KK. Nox proteins in signal transduction. Free Radic BiolMed 2009;47:1239–53.

[70] Hernandes MS, Britto LR. NADPH oxidase and neurodegeneration. CurrNeuropharmacol 2012;10:321–7.

[71] Whiley L, Sen A, Heaton J, Proitsi P, García-Gómez D, Leung R, et al. Evidence ofaltered phosphatidylcholine metabolism in Alzheimer’s disease. NeurobiolAging 2014;35:271–8.

[72] Jeng W, Loniewska MM, Wells PG. Brain glucose-6-phosphate dehydrogenaseprotects against endogenous oxidative DNA damage and neurodegeneration inaged mice. ACS Chem Neurosci 2013;17:1123–32.

[73] Mavroudis IA, Manani MG, Petrides F, Petsoglou K, Njau SD, Costa VG, et al.Dendritic and spinal pathology of the Purkinje cells from the human cerebellarvermis in Alzheimer’s disease. Psychiatr Danub 2013;25:221–6.

[74] Wang Q, Xiao B, Cui S, Song H, Qian Y, Dong L, et al. Triptolide treatmentreduces Alzheimer’s disease (AD)-like pathology through inhibition of BACE1in a transgenic mouse model of AD. Dis Model Mech 2014;7:1385–95.

[75] Hensley K, Harris-White ME. Redox regulation of autophagy in healthy brainand neurodegeneration. Neurobiol Dis Mar 2015; 11. pii: S0969-9961(15)00063-7. doi:http://dx.doi.org/10.1016/j.nbd.2015.03.002.

[76] Huang HC, Tang D, Lu SY, Jiang ZF. Endoplasmic reticulum stress as a novelneuronal mediator in Alzheimer’s disease. Neurol Res 2015;37:366–74.

[77] Száraz P, Bánhegyi G, Benedetti A. Altered redox state of luminal pyridinenucleotides facilitates the sensitivity towards oxidative injury and leads toendoplasmic reticulum stress dependent autophagy in HepG2 cells. Int JBiochem Cell Biol J 2010;42:157–66.

[78] Lavery GG, Walker EA, Turan N, Rogoff D, Ryder JW, Shelton JM, et al. Deletionof hexose-6-phosphate dehydrogenase activates the unfolded proteinresponse pathway and induces skeletal myopathy. J Biol Chem2008;283:8453–61.

[79] Zielinska AE, Walker EA, Stewart PM, Lavery GG. Biochemistry and physiologyof hexose-6-phosphate knockout mice. Mol Cell Endocrinol 2011;10:213–8.

[80] Senesi S, Csala M, Marcolongo P, Fulceri R, Mandl J, Banhegyi G, et al. Hexose-6-phosphate dehydrogenase in the endoplasmic reticulum. Biol Chem2010;391:1–8.

[81] Abdel Moneim AE. Oxidant/antioxidant imbalance and the risk of Alzheimer’sdisease. Curr Alzheimer Res 2015 [Epub ahead of print].