Abstract
Alzheimer’s, a degenerative cause of the brain cells, is called as a progressive neurodegenerative disease and appears to have a heterogeneous etiology with main emphasis on amyloid-cascade and hyperphosphorylated tau-cascade hypotheses, that are directly linked with macromolecules called enzymes such as β- & γ-secretases, colinesterases, transglutaminases, and glycogen synthase kinase (GSK-3), cyclin-dependent kinase (cdk-5), microtubule affinity-regulating kinase (MARK). The catalytic activity of the above enzymes is the result of cognitive deficits, memory impairment and synaptic dysfunction and loss, and ultimately neuronal death. However, some other enzymes also lead to these dysfunctional events when reduced to their normal activities and levels in the brain, such as α- secretase, protein kinase C, phosphatases etc; metabolized to neurotransmitters, enzymes like monoamine oxidase (MAO), catechol-O-methyltransferase (COMT) etc. or these abnormalities can occur when enzymes act by other mechanisms such as phosphodiesterase reduces brain nucleotides (cGMP and cAMP) levels, phospholipase A2: PLA2 is associated with reactive oxygen species (ROS) production etc. On therapeutic fronts, several significant clinical trials are underway by targeting different enzymes for development of new therapeutics to treat Alzheimer’s, such as inhibitors for β-secretase, GSK-3, MAO, phosphodiesterase, PLA2, cholinesterases etc, modulators of α- & γ-secretase activities and activators for protein kinase C, sirtuins etc. The last decades have perceived an increasing focus on findings and search for new putative and novel enzymatic targets for Alzheimer’s. Here, we review the functions, pathological roles, and worth of almost all the Alzheimer’s associated enzymes that address to therapeutic strategies and preventive approaches for treatment of Alzheimer’s.
Keywords: Alzheimer's, memory and cognition, enzymes, enzymatic targets, therapeutics, clinical trials.
Graphical Abstract
[3]
Lahiri DK, Farlow MR, Sambamurti K, Greig HN, Giacobini E, Schneider LS. A critical analysis of new molecular targets and strategies for drug developments in Alzheimer’s disease. Curr Drug Targets 2003; 4: 97-112.
[4]
Pahnke J, Walker LC, Scheffler K, Krohn M. Alzheimer’s disease and blood–brain barrier function-Why have anti-b-amyloid therapies failed to prevent dementia progression? Neurosci Biobehav Rev 2009; 33: 1099-108.
[5]
Larson EB, Kukull WA, Katzman RL. Cognitive impairment: Dementia and Alzheimer’s disease. Annu Rev Public Health 1992; 13: 431-49.
[8]
Craig LA, Hong NS, McDonald RJ. Revisiting the cholinergic hypothesis in the development of Alzheimer’s disease. Neurosci Biobehav Rev 2011; 35: 1397-409.
[9]
Bezprozvanny I, Mattson MP. Neuronal calcium mishandling and the pathogenesis of Alzheimer’s disease. Trends Neurosci 2008; 31: 454-63.
[10]
Espinet C, Gonzalo H, Fleitas C, Menal MJ, Egea J. Oxidative stress and neurodegenerative diseases: A neurotrophic approach. Curr Drug Targets 2015; 16: 20-30.
[11]
Trepanier CH, Milgram NW. Neuroinflammation in Alzheimer’s disease: are NSAIDs and selective COX-2 inhibitors the next line of therapy? J Alzheimers Dis 2010; 21: 1089-99.
[12]
Bonda DJ, Lee H, Blair JA, Zhu X, Perry G, Smith MA. Role of metal dyshomeostasis in Alzheimer’s disease. Metallomics 2011; 3: 267-70.
[13]
Blonz ER. Alzheimer’s disease as the product of a progressive energy deficiency syndrome in the central nervous system: The neuroenergetic hypothesis. J Alzheimers Dis 2017.
[http://dx.doi.org/10.3233/JAD-170549]
[http://dx.doi.org/10.3233/JAD-170549]
[14]
Vassar R, Citron M. Aβ-generating enzymes: Recent advances in β- and ץ-secretase research. Neuron 2000; 27: 419-22.
[15]
Maloney B, Lahiri DK. The Alzheimer’s amyloid beta-peptide binds a specific DNA Abeta-interacting domain in the APP, BACE1, and APOE promoters in a sequence-specific manner: Characterizing a new regulatory motif. Gene 2011; 488: 1-12.
[17]
Poletti M, Enrici I, Adenzato M. Cognitive and affective Theory of Mind in neurodegenerative diseases: Neuropsychological, neuroanatomical and neurochemical levels. Neurosci Biobehav Rev 2012; 36: 2147-64.
[18]
Ballard C, Gauthier S, Corbett A, Brayne C, Aarsland D, Jones E. Alzheimer’s disease. Lancet 2011; 377: 1019-31.
[19]
Martin A, DeVivo G, Gentile V. Possible role of the transglutaminases in the pathogenesis of Alzheimer’s disease and other neurodegenerative diseases. Int J Alzheimers Dis 2011; 2011: 865432.
[20]
Rohn TT, Head E, Su JH, et al. Correlation between caspase activation and neurofibrillary tangle formation in Alzheimer’s disease. Am J Pathol 2011; 158: 189-98.
[21]
Theofilas P, Ehrenberg AJ, Nguy A, et al. Probing the correlation of neuronal loss, neurofibrillary tangles, and cell death markers across the Alzheimer’s disease Braak stages: A quantitative study in humans. Neurobiol Aging 2018; 61: 1-12.
[22]
Blokland A, Schreiber R, Prickaerts J. Improving memory: A role for phosphodiesterases. Curr Pharm Des 2006; 12: 2511-23.
[23]
Naoi M, Maruyam W, Inaba-Hasegawa K, Akao Y. Type A monoamine oxidase regulates life and death of neurons in neurodegeneration and neuroprotection. Int Rev Neurobiol 2011; 100: 85-106.
[24]
Calati R, Porcelli S, Giegling I, et al. Catecholo-methyltransferase gene modulation on suicidal behavior and personality traits: Review, meta-analysis and association study. J Psychiatr Res 2010; 45: 309-21.
[25]
Bachurin SO, Bovina EV, Ustyugov AA. Drugs in clinical trials for Alzheimer’s disease: The major trends. Med Res Rev 2017; 37: 1186-225.
[26]
Turner RS, Thomas RG, Craft S, van Dyck CH, et al. A randomized, double-blind, placebo-controlled trial of resveratrol for Alzheimer disease. Neurology 2015; 85: 1383-91.
[27]
Esler WP, Wolfe MS. A portrait of alzheimer secretases-new features and familiar faces. Science 2001; 293: 1449-54.
[28]
Strooper BD, Vassar R, Golde T. The secretases: Enzymes with therapeutic potential in Alzheimer disease. Nat Rev Neurol 2010; 6: 99-107.
[30]
Fahrenholz F, Postina R. α-Secretase activation - an approach to alzheimer’s disease therapy. Neurodegener Dis 2006; 3: 255-61.
[31]
Selkoe DJ. Amyloid β-protein and the genetics of Alzheimer’s disease. J Biol Chem 1996; 27: 18595-8.
[32]
Koike H, Tomioka S, Sorimachi H, et al. Membrane-anchored metalloprotease MDC9 has an α-secretase activity responsible for processing the amyloid precursor protein. Biochem J 1999; 343: 371-5.
[34]
Kojro E, Fahrenholz F. The non-amyloidogenic pathway: Structure and function of α-secretases. Subcell Biochem 2005; 38: 105-27.
[35]
Obregon D, Hou H, Deng J, et al. Soluble amyloid precursor protein-α modulates β-secretase activity and amyloid-β generation. Nat Commun 2012; 777: 1-9.
[37]
Seidaha NG, Chretienb M. Proprotein and prohormone convertases: a family of subtilases generating diverse bioactive polypeptides. Brain Res 1999; 848: 45-62.
[38]
Anders A, Gilbert S, Garten W, Postina R, Fahrenholz F. Regulation of the α-secretase ADAM10 by its prodomain and proprotein convertases. FASEB J 2001; 15: 1837-49.
[39]
Goodman AB, Pardee AB. Evidence for defective retinoid transport and function in late onset Alzheimer’s disease. Proc Natl Acad Sci USA 2003; 100: 2901-5.
[40]
Endres K, Postina R, Schroeder A, Mueller U, Fahrenholz F. Shedding of the amyloid precursor protein-like protein APLP2 by disintegrin-metalloproteinases. FEBS J 2005; 272: 5808-20.
[41]
Prinzen C, Muller U, Endres K, Fahrenholz F, Postina R. Genomic structure and functional characterization of the human ADAM10 promoter. FASEB J 2005; 19: 1522-4.
[42]
Shackleton B, Crawford F, Bachmeier C. Apolipoprotein E-mediated modulation of ADAM10 in Alzheimer’s disease. Curr Alzheimer Res 2017; 14: 578-85.
[43]
Nitsch RM, Deng M, Tennis M, Schoenfeld D, Growdon JH. The selective muscarinic M1 agonist AF102B decreases levels of total Aβ in cerebrospinal fluid of patients with Alzheimer’s disease. Ann Neurol 2000; 48: 913-8.
[44]
Etcheberrigaray R, Tan M, Dewachter I, et al. Therapeutic effects of PKC activators in Alzheimer’s disease transgenic mice. Proc Natl Acad Sci USA 2004; 101: 11141-6.
[45]
Kojro E, Postina R, Buro C, Meiringer C, Gehrig-Burger K, Fahrenholz F. The neuropeptide PACAP promotes α-secretase pathway for processing Alzheimer amyloid precursor protein. FASEB J •••; 206(20): 512-4.
[46]
Kojro E, Gimpl G, Lammich S, Marz W, Fahrenholz F. Low cholesterol stimulates the nonamyloidogenic pathway by its effect on the α-secretase ADAM 10. Proc Natl Acad Sci USA 2001; 98: 5815-20.
[47]
Hoglund K, Thelen KM, Syversen S, et al. The effect of simvastatin treatment on the amyloid precursor protein and brain cholesterol metabolism in patients with Alzheimer’s disease. Dement Geriatr Cogn Disord 2005; 19: 256-65.
[48]
Paolo GD, Kim T. Linking lipids to Alzheimer’s disease: Cholesterol and beyond. Nat Rev Neurosci 2011; 12: 284-96.
[49]
Howlett DR, Simmons DL, Dingwall C, Christie G. In search of an enzyme: the β-secretase of Alzheimer’s disease is an aspartic proteinase. Trends Neurosci 2000; 23: 565-71.
[50]
MacLeod R, Hillert E, Cameron RT, Baillie GS. The role and therapeutic targeting of α-, β- and γ-secretase in Alzheimer’s disease. Future Sci OA 2015; 1: FSO11.
[51]
Yan R, Han P, Miao H, Greengard P, Xu H. The transmembrane domain of the Alzheimer’s β-secretase (BACE1) determines its late Golgi localization and access to β-amyloid precursor protein (APP) substrate. J Biol Chem 2001; 276: 36788-96.
[52]
Barao S, Moechars D, Lichtenthaler SF. De Strooper. BACE1 physiological functions may limit its use as therapeutic target for Alzheimer’s disease. Trends Neurosci 2016; 39: 158-69.
[53]
Kitazume S, Tachida Y, Oka R, Shirotani K, Saido TC, Hashimoto Y. Alzheimer’s β-secretase, β-site amyloid precursor protein-cleaving enzyme, is responsible for cleavage secretion of a Golgi-resident sialyltransferase. Proc Natl Acad Sci USA 2001; 98: 13554-9.
[54]
Lictenthaler SF, Dominguez D, Westmever GG, et al. The cell adhesion protein P-selectin glycoprotein ligand-1 is a substrate for the aspartyl protease BACE1. J Biol Chem 2003; 278: 48713-9.
[55]
Eggert S, Paliga K, Soba P, et al. The proteolytic processing of the amyloid precursor protein gene family members APLP-1 and APLP-2 involves α-, β-, γ-, and ε-like cleavages: Modulation of APLP-1 processing by n-glycosylation. J Biol Chem 2004; 279: 18146-56.
[56]
Pastorino L, Ikin AF, Lamprianou S, et al. BACE (β-secretase) modulates the processing of APLP2 in vivo. Mol Cell Neurosci 2004; 25: 642-9.
[57]
Von Arnim CA, Kinoshita A, Peltan ID, et al. The low density lipoprotein receptor-related protein (LRP) is a novel β-secretase (BACE1) substrate. J Biol Chem 2005; 280: 17777-85.
[58]
Kim DY, Carey BW, Wang H, et al. BACE1 regulates voltage-gated sodium channels and neuronal activity. Nat Cell Biol 2007; 9: 755-64.
[59]
Hu X, He W, Diaconu C, et al. Genetic deletion of BACE1 in mice affects remyelination of sciatic nerves. FASEB J 2008; 22: 2970-80.
[60]
Hu X, Hicks CW, He W, et al. Bace1 modulates myelination in the central and peripheral nervous system. Nat Neurosci 2006; 9: 1520-5.
[61]
Cai XD, Golde TE, Younkin SG. Release of excess amyloid-β protein from a mutant amyloid beta protein precursor. Science 1993; 259: 514-6.
[62]
Zhong Z, Ewers M, Teipel S, et al. Levels of β-Secretase (BACE1) in cerebrospinal fluid as a predictor of risk in mild cognitive impairment. Arch Gen Psychiatry 2007; 64: 718-26.
[63]
Ewers M, Zhong Z, Katharina B, et al. Increased CSF-BACE1 activityis associated with ApoE-ε4 genotype in subjects with mild cognitive impairment and Alzheimer’s disease. Brain 2008; 131: 1252-8.
[64]
Reinvang I, Espeseth T, Westlye LT. APOE-related biomarker profiles in non-pathological aging and early phases ofAlzheimer’s disease. Neurosci Biobehav Rev 2013; 37: 1322-35.
[65]
Hajjari SN, Mehdizadeh M, Saeed S, Dariush S, Teimourian S, Baradaran B. Secretases-related miRNAs in Alzheimer’s disease: new approach for biomarker discovery. Neurol Sci 2017; 38: 1921-6.
[66]
Li Rena, Li R, Lindholm K, et al. Amyloid-β peptide load is correlated with increased β-secretase activity in sporadic Alzheimer’s disease patients. Proc Natl Acad Sci USA 2004; 101: 3632-7.
[67]
Seirant M, et al. RNA interference in silencing of genes of Alzheimer’s disease in cellular and rat brain models. Oxford University¶
Press, Nucleic Acids Symposium Series No. 52: 41-2.
[68]
Seirant M, et al. Evaluation of BACE1 Silencing in CellularModels. Int J Alzheimers Dis 2009; 1-10.
[http://dx.doi.org/10.4061/2009/257403]
[http://dx.doi.org/10.4061/2009/257403]
[69]
Kulshreshtha A, Piplani P. Current pharmacotherapy and putative disease-modifying therapy for Alzheimer’s disease. Neurol Sci 2016; 37: 1403-35.
[70]
Silva T, Reis J, Teixeira J, Borges F. Alzheimer’s disease, enzyme targets and drug discovery struggles: From natural products to drug prototypes. Ageing Res Rev 2014; 15: 116-45.
[71]
Zhou S, Zhou H, Walian PJ, Jap BK. Regulation of γ-secretase activity in Alzheimer’s disease. Biochemistry 2007; 46: 2553-63.
[72]
Lichtenthaler SF. Ectodomain shedding of the Amyloid precursor protein: cellular control mechanisms and novel modifiers. Neurodegener Dis 2006; 3: 262-9.
[73]
Xie Z, Romano DM, Kovacs DM, Tanzi RE. Effects of RNA interference-mediated silencing of γ-secretase complex components on cell sensitivity to caspase-3 activation. J Biol Chem 2004; 279: 34130-7.
[74]
Weidemann A, Eggert S, Reinhard FB, et al. A novel ε-cleavage within the transmembrane domain of the Alzheimer amyloid precursor protein demonstrates homology with Notch processing. Biochemistry 2002; 41: 2825-35.
[75]
Willem M, Sabina T, Busche MA, et al. η-Secretase processing of APP inhibits neuronal activity in the hippocampus. Nature 2015; 526: 443-7.
[76]
Nalivaeva NN, Fisk LR, Belyaev ND, Turner AJ. Amyloid-degrading enzymes as therapeutic targets in Alzheimer’s disease. Curr Alzheimer Res 2008; 5: 212-24.
[77]
Turner AJ, Fisk LR, Nalivaeva NN. Targeting amyloid-degrading enzymes as therapeutic strategies in neurodegeneration. Ann N Y Acad Sci 2004; 1035: 1-20.
[78]
Birkedal-Hanson H, Moore WG, Bodden MK, et al. Matrix metalloproteinses: A review. Crit Rev Oral Biol Med 1993; 4: 197-250.
[79]
Gottschall PE, Deb S. Regulation of matrix metalloproteinase expression in astrocytes, microglia and neurons. Neuroimmunomodulation 1996; 3: 69-75.
[80]
Lorenzl S, Albers DS, Relkin N, et al. Increased plasma levels of matrix metalloproteinase-9 in patients with Alzheimer’s disease. Neurochem Int 2003; 43: 191-6.
[81]
Cauwe B, Van den Steen PE, Opdenakker G. The biochemical, biological, and pathological kaleidoscope of cell surface substrates processed by matrix metalloproteinases. Crit Rev Biochem Mol Biol 2007; 42: 113-85.
[82]
Yan P, Hu X, Song H, et al. Matrix metalloproteinase-9 degrades amyloid- fibrils in vitro and compact plaques in situ. J Biol Chem 2008; 281: 24566-74.
[83]
Yasojima K, Akiyama H, McGeer EG, McGeer PL. Reduced neprilysin in high plaque areas of Alzheimer brain: a possible relationship to deficient degradation of β-amyloid peptide. Neurosci Lett 2001; 297: 97-100.
[84]
Howell S, Nalbantoglu J, Crine P. Neutral endopeptidase can hydrolyze β-amyloid (1-40) but shows no effect on β-amyloid precursor protein metabolism. Peptides 1995; 16: 647-52.
[85]
Iwata N, Tsubuki S, Takaki Y, et al. Metabolic regulation of the brain Aβ by neprilysin. Science 2001; 292: 1550-2.
[86]
Marr RA, Guan H, Rockenstein E, et al. Neprilysin regulates amyloid β peptide levels. J Mol Neurosci 2004; 22: 5-11.
[87]
Zhou L, Liu J, Dong D, Wei C, Wang R. Dynamic alteration of neprilysin and endothelin-converting enzyme in age-dependent APPswe/PS1dE9 mouse model of Alzheimer’s disease. Am J Transl Res 2017; 9: 184-96.
[88]
Hafez D, Huang JY, Huynh AM, et al. Neprilysin-2 is an important β-amyloid degrading enzyme. Am J Pathol 2011; 178: 306-12.
[89]
Zhuravin IA, Nalivaeva NN, Kozlova DI, et al. The activity of blood serum cholinesterases and neprilysin as potential biomarkers of mild-cognitive impairment and Alzheimer’s disease. Zh Nevrol Psikhiatr Im S S Korsakova 2015; 115: 110-7.
[90]
Mzhavia N, Pan H, Che FY, Fricker LD, Devi LA. Characterization of endothelin-converting enzyme-2. Implication for a role in the nonclassical processing of regulatory peptides. J Biol Chem 2003; 278: 14704-11.
[91]
Qiu WQ, Walsh DM, Ye Z, et al. Insulin-degrading enzyme regulates extracellular levels of amyloid beta-protein by degradation. J Biol Chem 1998; 273: 32730-8.
[92]
Igor VK, Guarnera E, Wong JH, Frank E, Igor NB. Towards allosterically increased catalytic activity of insulin degrading enzyme (IDE) against amyloid peptides. Biochemistry 2016; 56: 228-39.
[93]
Olga P, Annika H, Grunec T, Andreas FH, Natalia R. Insulin-degrading enzyme: new therapeutic target for diabetes and Alzheimer’s disease. Ann Med 2016; 48: 614-24.
[94]
Sudilovsky A, Turnbull B, Croog SH, Crook T. Angiotensin converting enzyme and memory: Preclinical and clinical data. Int J Neurol 1987; 21-22: 145-62.
[95]
Kehoe PG, Russ C, McIlroy S, et al. Variation in DCP1, encoding ACE, is associated with susceptibility to Alzheimer disease. Nat Genet 1999; 21: 71-2.
[96]
Savaskan E, Hock C, Olivieri G, et al. Cortical alterations of angiotensin converting enzyme, angiotensin II and AT1 receptor in Alzheimer’s dementia. Neurobiol Aging 2001; 22: 541-6.
[97]
Hu J, Igarashi A, Kamata M, Nakagawa H. Angiotensin-converting enzyme degrades Alzheimer amyloid-β peptide (Aβ); retards Aβ aggregation, deposition, fibril formation; and inhibits cytotoxicity. J Biol Chem 2001; 276: 47863-8.
[98]
Hemming ML, Selkoe DJ. Amyloid β-protein is degraded by cellular angiotensin-converting enzyme (ACE) and elevated by an ACE inhibitor. J Biol Chem 2005; 280: 37644-50.
[99]
Zou K, Yamaguchi H, Akatsu H, et al. Angiotensin-converting enzyme converts amyloid β-protein 1-42 (Aβ1-42) to, Aβ1-40, and its inhibition enhances brain Aβ deposition. J Neurosci 2007; 27: 8628-35.
[100]
Hanes DS, Weir MR. Usefulness of ARBs and ACE inhibitors in the prevention of vascular dementia in the elderly. Am J Geriatr Cardiol 2007; 16: 175-82.
[101]
Kehoe PG, Hibbs E, Laura E. Palmer, Miners JS. Angiotensin-III is increased in Alzheimer’s disease in association with amyloid-β and tau pathology. J Alzheimers Dis 2017; 58: 203-14.
[102]
Nicholson DW. From bench to clinic with apoptosis-based therapeutic agents. Nature 2000; 407: 810-6.
[103]
Su JH, Anderson AJ, Cummings BJ, Cotman CW. Immunohistochemical evidence for DNA fragmentation in neurons in the AD brain. Neuroreport 1994; 5: 2529-33.
[104]
Gervais FG, Xu D, Robertson GS, et al. Involvement of caspases in proteolytic cleavage of Alzheimer’s amyloid-b precursor protein and amyloidogenic Aβ peptide formation. Cell 1999; 97: 395-406.
[105]
Wellington CL, Hayden MR. Caspases and neurodegeneration: On the cutting edge of new therapeutic approaches. Clin Genet 2000; 57: 1-10.
[106]
Roth KA. Caspases, apoptosis, and Alzheimer disease: Causation, correlation, and confusion. J Neuropathol Exp Neurol 2001; 60: 829-38.
[107]
Friedlander RM. Apoptosis and caspases in neurodegenerative diseases. N Engl J Med 2003; 348: 1365-75.
[108]
Gamblin TC, Chen F, Zambrano A, et al. Caspase cleavage of tau: linking amyloid and neurofibrillary tangles in Alzheimer’s disease. Proc Natl Acad Sci USA 2003; 100: 10032-7.
[109]
Chauvier D, Ankri S, Charriaut-Marlangue C, Casimir R, Jacotot E. Broad-spectrum caspase inhibitors: from myth to reality? Cell Death Differ 2007; 14: 387-91.
[110]
Kim HS, Suh YH. Minocycline and neurodegenerative diseases. Behav Brain Res 2009; 196: 168-79.
[111]
Bolaños JP, Almeida A, Stewart V. Nitric oxide-mediated mitochondrial damage in the brain: Mechanisms and implications for neurodegenerative diseases. J Neurochem 1997; 68: 2227-40.
[112]
Lee SC, Zhao ML, Hirano A, Dickson DW. Inducible Nitric Oxide Synthase Immunoreactivity in the Alzheimer’s Disease Hippocampus: Association with Hirano Bodies, Neurofibrillary Tangles, and Senile Plaques. J Neuropathol Exp Neurol 1999; 58: 1163-9.
[113]
Dennis EA. Diversity of group types, regulation, and function of phospholipase A2. J Biol Chem 1994; 269: 13057-60.
[114]
Ishii K, Muelhauser F, Liebl U, et al. Subacute NO generation induced by Alzheimer’s beta-amyloid in the living brain: Reversal by inhibition of the inducible NO synthase. FASEB J 2000; 14: 1485-9.
[115]
Law A, Gauthier S, Quirion R. Say NO to Alzheimer’s disease: the putative links between nitric oxide and dementia of the Alzheimer’s type. Brain Res Brain Res Rev 2001; 35: 73-96.
[116]
Fernandez-Vizarra P, Fernandez AP, Castro-Blanco S, et al. Expression of nitric oxide system in clinically evaluated cases of Alzheimer’s disease. Neurobiol Dis 2004; 15: 287-305.
[117]
Diaz A, Mendieta L, Zenteno E, Guevara J, Limon ID. The role of NOS in the impairment of spatial memory and damaged neurons in rats injected with amyloid beta 25–35 into the temporal cortex. Pharmacol Biochem Behav 2011; 98: 67-75.
[118]
Lorand L, Graham RM. Transglutaminases: Crosslinking enzymes with pleiotropic functions. Nat Rev Mol Cell Biol 2003; 4: 140-56.
[119]
Miller CC, Anderton BH. Transglutaminase and the Neuronal Cytoskeleton in Alzheimer’s Disease. J Neurochem 1986; 46: 1912-22.
[120]
Johnson GV, Cox TM, Lockhart JP, Zinnerman MD, Miller ML, Powers RE. Transglutaminase activity is increased in Alzheimer’s disease brain. Brain Res 1997; 751: 323-9.
[121]
Wang D, Dickson DW, Malter JS. Tissue transglutaminase, protein cross-linking and alzheimer’s disease: review and views. Int J Clin Exp Pathol 2008; 1: 5-18.
[122]
Wilhelmus MM, Grunberg SC, Bol JG, et al. transglutaminases and transglutaminase-catalyzed cross-links colocalize with the pathological lesions in alzheimer’s disease brain. Brain Pathol 2009; 19: 612-22.
[123]
Curro M, Ferlazzo N, Condello S, Caccamo D, Ientile R. Transglutaminase 2 silencing reduced the beta-amyloid-effects on the activation of human THP-1 cells. Amino Acids 2010; 39: 1427-33.
[124]
Huang X, Atwood CS, Moir RD, et al. Zinc-induced Alzheimer’s Abeta1-40 aggregation is mediated by conformational factors. J Biol Chem 1997; 272: 26464-70.
[125]
Atwood CS, Moir RD, Huang X, et al. Dramatic aggregation of Alzheimer abeta by Cu(II) is induced by conditions representing physiological acidosis. J Biol Chem 1998; 273: 12817-26.
[126]
Pomara N, Greenberg WM, Branford MD, Doraiswamy PM. Therapeutic implications of HPA axis abnormalities in Alzheimer’s disease: review and update. Psychopharmacol Bull 2003; 37: 120-34.
[127]
Green KN, Billings LM, Roozendaal B, McGaugh JL, LaFerla FM. Glucocorticoids increase amyloid beta and tau pathology in a mouse model of Alzheimer’s disease. J Neurosci 2006; 26: 9047-56.
[128]
Du J, Wang Y, Hunter R, et al. Dynamic regulation of mitochondrial function by glucocorticoids. Proc Natl Acad Sci USA 2009; 106: 3543-8.
[129]
Tomlinson JW, Walker EA, Bujalska IJ, et al. 11β hydroxysteroid dehydrogenase type1: A tissue specific regulator of glucocorticoid response. Endocr Rev 2004; 25: 831-66.
[130]
Mohler EG, Browman KE, et al. Acute inhibition of 11β-hydroxysteroid dehydrogenase type-1 improves memory in rodent models of cognition. J Neurosci 2011; 31: 5406-13.
[131]
Marek GJ, Katz DA, Meier A, et al. Efficacy and safety evaluation of HSD-1 inhibitor ABT-384 in Alzheimer’s disease. Alzheimers Dement 2013; 10: s364-73.
[132]
Sooy K. Cognitive and disease-modifying effects of 11ßhydroxysteroid dehydrogenase type 1 inhibition in male Tg2576 mice, a model of Alzheimer’s disease. Endocrinology 2015; 156: 4592-603.
[133]
Webster SP, McBride A, Binnie M, et al. Selection and early clinical evaluation of the brain-penetrant 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) inhibitor UE2343 (XanamemTM). Br J Pharmacol 2017.
[http://dx.doi.org/10.1111/bph.13699]
[http://dx.doi.org/10.1111/bph.13699]
[134]
Yan SD, Fu J, Soto C, et al. An intracellular protein that binds amyloid-β peptide and mediates neurotoxicity in Alzheimer’s disease. Nature 1997; 389: 689-95.
[135]
He XY, Wen GY, Merz G, et al. Abundant type10 17 beta-hydroxysteroid hydrogenase in the hippocampus of mouse Alzheimer’s disease model. Brain Res 2002; 99: 46-53.
[136]
Oppermann UC, Salim S, Tjernberg LO, Terenius L, Jörnvall H. Binding of Amyloid β-Peptide to Mitochondrial Hydroxyacyl-CoA Dehydrogenase (ERAB): Regulation of an SDR Enzyme Activity with Implications for Apoptosis in Alzheimer’s Disease. FEBS Lett 1999; 451: 238-42.
[137]
Lim Y-A, Grimm A, Giese M, et al. Inhibition of the Mitochondrial Enzyme ABAD Restores the Amyloid-b-Mediated Deregulation of Estradiol. PLoS One 2011; 6: e28887.
[138]
Yao J, Du H, Yan S, et al. InhibitionofAmyloi-β (Aβ) Peptide Binding Alcohol Dehydrogenase-Aβ Interaction Reduces Aβ Accumulation and Improves Mitochondrial Function in a Mouse Model of Alzheimer’s disease. J Neurosci 2011; 31: 2313-20.
[139]
Valasani KR, Sun Q, Hu G, et al. (2014) Identification of Human ABAD Inhibitors for Rescuing Aβ-Mediated Mitochondrial Dysfunction. Curr Alzheimer Res 11: 128-36.
[140]
Zakaria A, Hamdi N, Abdel-Kader RM. Methylene Blue Improves Brain Mitochondrial ABAD Functions and Decreases Aβ in a Neuroinflammatory Alzheimer’s Disease Mouse Model. Mol Neurobiol 2015; 53: 1220-8.
[141]
Hroch L, Guest P, Benek O, et al. Synthesis and evaluation of frentizole-based indolyl thiourea analogues as MAO/ABAD inhibitors for Alzheimer’s disease treatment. Bioorg Med Chem 2016; 25: 1143-52.
[142]
Aitken L, Baillie G, Pannifer A, et al. In Vitro Assay Development and HTS of Small-Molecule Human ABAD/17β-HSD10 Inhibitors as Therapeutics in Alzheimer’s disease. SLAS Discov 2017; 22: 676-85.
[143]
Hunter T, Sefton BM. Transforming gene product of Rous sarcoma virus phosphorylates tyrosine. Proc Natl Acad Sci USA 1980; 77: 1311-5.
[144]
Gertler FB, Bennet RL, Clark MJ, Hoffman FM. Drosophila abl tyrosine kinase in embryonic CNS axons: a role in axonogenesis is revealed through dosage-sensitive interactions with disabled. Cell 1989; 58: 103-13.
[145]
Shapiro IP, Masliah E, Saitoh T. Altered Protein Tyrosine Phosphorylation in Alzheimer’s Disease. J Neurochem 1991; 56: 1154-66.
[146]
Guan J, Shalloway D. Regulation of focal adhesion-associated protein tyrosine kinase by both cellular adhesion and oncogenic transformation. Nature 1992; 358: 690-3.
[147]
Luo YQ, Hirashima N, Li YH, Alkon DL. Physiological levels of fl-amyloid increase tyrosine phosphorylation and cytosolic calcium. Brain Res 1995; 681: 65-74.
[148]
Schipper RG, Verhofstad AA. Distribution patterns of ornithine decarboxylase in cells and tissues: facts, problems, and postulates. J Histochem Cytochem 2002; 50: 1143-60.
[149]
Johnson TD. Modulation of channel function by polyamines. Trends Pharmacol Sci 1996; 17: 22-7.
[150]
Morrison LD, Cao XC, Kish SJ. Ornithine decarboxylase in human brain: influence of aging, regional distribution, and Alzheimer’s disease. J Neurochem 1998; 71: 288-94.
[151]
Yatin SM, Yatin M, Aulick T, Ain KB, Butterfield DA. Alzheimer’s amyloid beta-peptide associated free radicals increase rat embryonic neuronal polyamine uptake and ornithine decarboxylase activity: protective effect of vitamin E. Neurosci Lett 1999; 263: 17-20.
[152]
Pajunen AE, Hietala OA, Virransalo EL, Piha RS. Ornithine decarboxylase and adenosylmethionine decarboxylase in mouse brain- effect of electrical stimulation. J Neurochem 1978; 30: 261-83.
[153]
Avila J, Wandosell F, Hernández F. Role of glycogen synthase kinase-3 in Alzheimer’s disease pathogenesis and glycogen synthase kinase-3 inhibitors. Expert Rev Neurother 2010; 10: 703-10.
[154]
Grimes CA, Jope RS. The multifaceted roles of glycogen synthase kinase 3beta in cellular signaling. Prog Neurobiol 2001; 65: 391-426.
[155]
Hooper C, Markevich V, Plattner F, et al. Glycogen synthase kinase-3 inhibition is integral to long-term potentiation. Eur J Neurosci 2007; 25: 81-6.
[156]
Pei JJ, Braak E, Braak H, et al. Distribution of active glycogen synthase kinase 3β (GSK-3β) in brains staged for Alzheimer disease neurofibrillary changes. J Neuropathol Exp Neurol 1999; 58: 1010-9.
[157]
Hurtado DE, et al. Selectively Silencing GSK-3 Isoforms Reduces Plaques and Tangles in Mouse Models of Alzheimer’s disease. J Neurosci 2012; 32: 7392-402.
[158]
Kobayashi S, Ishiguro K, Omori A, et al. A cdc2-related kinase PSSALRE/cdk5 is homologous with the 30 kDa subunit of tau protein kinase II, a prolinedirected protein kinase associated with microtubule. FEBS Lett 1993; 335: 171-5.
[159]
Smith DS, Tsai LH. Cdk5 behind the wheel: a role in trafficking and transport? Trends Cell Biol 2002; 12: 28-36.
[160]
Allal B, Einar MS, Pavan KK. Tau as a Therapeutic Target for Alzheimer’s Disease. Curr Alzheimer Res 2011; 8: 666-77.
[161]
Ahlijanian MK, Barrezueta NX, Williams RD, et al. Hyperphosphorylated tau and neurofilament and cytoskeletal disruptions in mice overexpressing human p25, an activator of cdk5. Proc Natl Acad Sci USA 2000; 97: 2910-5.
[162]
Cruz JC, Tseng HC, Goldman JA, Shih H, Tsai LH. Aberrant Cdk5 activation by p25 triggers pathological events leading to neurodegeneration and neurofibrillary tangles. Neuron 2003; 40: 471-83.
[163]
Piedrahita D, et al. Silencing of CDK5 Reduces Neurofibrillary Tangles in Transgenic Alzheimer’s Mice. J Neurosci 2010; 30: 13966-76.
[164]
Lopez-tobon A, et al. Silencing of CDK5 as potential therapy for Alzheimer’s disease. Rev Neurosci 2011; 22: 143-52.
[165]
Burnett G, Kennedy EP. The enzymatic phosphorylation of proteins. J Biol Chem 1954; 211: 969-80.
[168]
Chauhan A, Chauhan VP, Murakami N, Brockerhoff H, Wisniewski HM. Amyloid β-protein stimulates casein kinase I and casein kinase II activities. Brain Res 1993; 629: 47-52.
[169]
Diaz-Nido J, Serrano L, Mondez E, Avila J. A casein kinase II-related activity is involved in phosphorylation of micro- tubule-associated protein MAP-1B during neuroblastoma cell differentiation. J Cell Biol 1988; 106: 2057-65.
[170]
Walter J, Schindzielorz A, Hartung B, Haass C. Phosphorylation of the β-amyloid precursor protein at the cell surface by ectocasein kinases 1 and 2. J Biologic Chem 2000; 275: 23523-9.
[171]
Perez DI, Gil C, Martinez A. Protein Kinases CK1 and CK2 as New Targets for Neurodegenerative Diseases. Med Res Rev 2011; 31: 924-54.
[172]
Li Guibin, Yin H, Kuret J. Casein kinase 1 delta phosphorylates Tau and disrupts its binding to microtubules. J Biol Chem 2004; 279: 15938-45.
[173]
Hanger DP, Byers HL, Wray S, et al. Novel phosphorylation sites in Tau from Alzheimer brain support a role for casein kinase-1 in disease pathogenesis. J Biol Chem 2007; 282: 23645-54.
[174]
Oumata N, Bettayeb K, Ferandin Y, et al. Roscovitine-derived, dual-specificity inhibitors of cyclin-dependent kinases and casein kinases 1. J Med Chem 2008; 51: 5229-42.
[175]
Serrano L, Hernandez MA, Diaz-Nido J, Avila J. Association of casein kinase II with microtubules. Exp Cell Res 1989; 181: 263-72.
[176]
Iimoto DS, Masliah E, DeTeresa R, Terry RD, Saitoh T. Aberrant casein kinase II in Alzheimer’s disease. Brain Res 1989; 507: 273-80.
[177]
Litchfield DW. Protein kinase CK2: structure, regulation and role in cellular decisions of life and death. Biochem J 2003; 369: 1-15.
[178]
Singh NN, Ramji DP. Transforming growth factor-beta-induced expression of the apolipoprotein E gene requires c-Jun N-terminal kinase, p38 kinase, and casein kinase 2. Arterioscler Thromb Vasc Biol 2006; 26: 1323-9.
[179]
Kramerov AA, Saghizadeh M, Pan H, et al. Expression of protein kinase CK2 in astroglial cells of normal and neovascularized retina. Am J Pathol 2006; 168: 1722-36.
[180]
Rosenberger AF, Morrema TH, Gerritsen WH, et al. Increased occurrence of protein kinase CK2 in astrocytes in Alzheimer’s disease pathology. J Neuroinflammation 2016; 13: 1-14.
[181]
Matenia D, Mandelkow EM. The tau of MARK: A polarized view of the cytoskeleton. Trends Biochem Sci 2009; 34: 332-42.
[182]
Tassan JP, Le GX. An overview of the KIN1/PAR-1/MARK kinase family. Biol Cell 2004; 96: 193-9.
[183]
Wu Q, DiBona VL, Bernard LP, Zhang H. The polarity protein partitioning-defective1 (PAR-1) regulates dendritic spine morphogenesis through phosphorylating postsynaptic density protein 95 (PSD-95). J Biol Chem 2012; 287: 30781-8.
[184]
Biernat J, Wu YZ, Timm T, et al. Protein kinase MARK/PAR-1 is required for neurite outgrowth and establishment of neuronal polarity. Mol Biol Cell 2002; 13: 4013-28.
[185]
Meijer L, Thunnissen AM, White AW, et al. Inhibition of cyclin-dependent kinases, GSK-3beta and CK1 by hymenialdisine, a marine sponge constituent. Chem Biol 2000; 7: 51-63.
[186]
Timm T, Balusamy K, Li X, Biernat J, Mandelkow E, Mandelkow EM. Glycogen synthase kinase (GSK) 3beta directly phosphorylates Serine 212 in the regulatory loop and inhibits microtubule affinity-regulating kinase (MARK) 2. J Biol Chem 2008; 283: 18873-82.
[187]
Song J, Park KA, Lee WT, Lee JE. Apoptosis signal regulating kinase 1 (ASK1): Potential as a therapeutic target for Alzheimer’s disease. Int J Mol Sci 2014; 15: 2119-29.
[188]
Hueber AO, Zornig M, Lyon D, Suda T, Nagata S, Evan GI. Requirement for the CD95 receptor-ligand pathway in c-Myc-induced apoptosis. Science 1997; 278: 1305-9.
[189]
Peel AL, Sorscher N, Kim JY, Galvan V, Chen S, Bredesen DE. Tau phosphorylation in Alzheimer’s disease: Potential involvement of an APP-MAP kinase complex. Neuromol Med 2004; 5: 205-18.
[190]
Cholerton B, Baker LD, Craft S. Insulin, cognition, and dementia. Eur J Pharmacol 2013; 719: 170-9.
[191]
Nishikawa T, Kukidome D, Sonoda K, et al. Impact of mitochondrial ROS production in the pathogenesis of insulin resistance. Diabetes Res Clin Pract 2007; 77: S161-4.
[192]
Cheon SY, Cho KJ, Song J, Kim GW. Knockdown of apoptosis signal-regulating kinase-1 affects ischaemia-induced astrocyte activation and glial scar formation. Eur J Neurosci 2016; 43: 912-22.
[193]
Dhillon AS, Hagan S, Rath O, Kolch W. AP kinase signalling pathways in cancer. Oncogene 2007; 26: 3279-90.
[194]
Kim EK, Choi E. Compromised MAPK signaling in human diseases: an update. Arch Toxicol 2015; 89: 867-82.
[195]
Lee JK, Kim NJ. Recent advances in the inhibition of p38 MAPK as a potential strategy for the treatment of Alzheimer’s disease. Molecules 2017; 22: E1287.
[196]
Gong CX, Liu F, Grundke-Iqbal I, Iqbal K. Post-translational modifications of tau protein in Alzheimer’s disease. J Neural Transm (Vienna) 2005; 112: 813-38.
[197]
Godoy JA, Rios JA, Zolezzi JM, Braidy N, Inestrosa NC. Signaling pathway cross talk in Alzheimer’s disease. Cell Commun Signal 2014; 12: 23.
[198]
Soreq H, Seidman S. Acetylcholinesterase- new roles for an old actor. Nature 2001; 2: 294-302.
[199]
Rees TM, Brimijoin S. The role of acetylcholinesterase in the pathogenesisof Alzheimer’s disease. Drugs Today (Barc) 2003; 39: 75-83.
[200]
Silver A. A histochemical investigation of cholinesterases at neuromuscular junctions in mammalian and avian muscle. J Physiol 1963; 169: 386-93.
[201]
Francis PT, Palmer AM, Snape M, Wilcock GK. The cholinergic hypothesis of Alzheimer’s disease: A review of progress. J Neurol Neurosurg Psychiatry 1999; 66: 137-47.
[202]
Schliebs R, Arendt T. The significance of the cholinergic system in the brainduring aging and in Alzheimer’s disease. J Neural Transm (Vienna) 2006; 113: 1625-44.
[203]
Schliebs R, Arendt T. The cholinergic system in aging and neuronal degen-eration. Behav Brain Res 2011; 221: 555-63.
[204]
Inestrosa NC, Alvarez A, Perez CA, et al. Acetylcholinesterase accelerates assembly of amyloid-β peptides into Alzheimer’s fibrils: possible role of the peripheral site of the enzyme. Neuron 1996; 16: 881-91.
[205]
Munoz FJ, Inestrosa NC. Neurotoxicity of acetylcholinesterase amyloid-β peptide aggregates is dependent on the type of Aβ peptide and the AChE concentration present in the complexes. FEBS Lett 1999; 450: 205-9.
[206]
Perry EK, Gibson PH, Blessed G, Perry RH, Tomlinson BE. Neurotransmitter enzyme abnormalities in senile dementia. Choline acetyltransferase and glutamic acid decarboxylase activities in necropsy brain tissue. J Neurol Sci 1977; 34: 247-65.
[207]
Augustinsson KB, Nachmansohn D. Distinction between acetylcholinesterase and other choline ester-splitting enzymes. Science 1949; 110: 98-9.
[208]
Li B, Stribley JA, Ticu A, et al. Abundant tissue butyrylcholinesterase and its possible function in the acetylcholinesterase knockout mouse. J Neurochem 2000; 75: 1320-31.
[209]
Kennedy BP, Ziegler MG, Alford M, Hansen LA, Thal LJ, Masliah E. Early and persistent alterations in frontal cortex MAO A and B in Alzheimer’s disease. J Neural Transm (Vienna) 2013; 110: 789-801.
[210]
Naoi M, Maruyam W, Inaba-Hasegawa K. Type A and B Monoamine Oxidase in Age-Related Neurodegenerative Disorders: Their Distinct Roles in Neuronal Death and Survival. Curr Top Med Chem 2012; 12: 2177-88.
[211]
Naoi M, Maruyama W, Shamoto-Nagai M. Type A and B monoamine oxidases distinctly modulate signal transduction pathway and gene expression to regulate brain function and survival of neurons. J Neural Transm 2017.
[http://dx.doi.org/10.1007/s00702-017-1832-6]
[http://dx.doi.org/10.1007/s00702-017-1832-6]
[212]
Vevera J, Stopkova R, Bes M, et al. COMT polymorphisms in impulsively violent offenders with antisocial personality disorder. Neuroendocrinol Lett 2009; 30: 753-6.
[213]
Sweet RA, Devlin B, Pollock BG, et al. Catechol-O-methyltransferase haplotypes are associated with psychosis in Alzheimer disease. Mol Psychiatry 2005; 10: 1026-36.
[214]
Huang G, Dragan M, Freeman D, Wilson JX. Activation of catechol-O-methyltransferase in astrocytes stimulates homocysteine synthesis and export to neurons. Glia 2005; 51: 47-55.
[216]
Yan W, Zhao C, Lu S, Tang B. Association between polymorphism of COMT gene (Val158Met) with Alzheimer’s disease: An update analysis. J Neurol Sci 2016; 361: 250-5.
[217]
Shearman MS, Shinomura T, Oda T, Nishizuka Y. Synaptosomal protein kinase C subspecies: A. Dynamic changes in the hippocampus and cerebellar cortex concomitant with synaptogenesis. J Neurochem 1991; 56: 1255-62.
[218]
Nelson TJ, Collin C, Alkon DL. Isolation of a G protein that is modified by learning and reduces potassium currents in Hermissenda. Science 1990; 247: 1479-83.
[219]
Hongpaisan J, Alkon DL. A structural basis for enhancement of long-term associative memory in single dendritic spines regulated by PKC. Proc Natl Acad Sci USA 2007; 104: 19571-6.
[220]
Khan TK, Sen A, Hongpaisan J, Lim CS, Nelson TJ, Alkon DL. PKC epsilon deficits in Alzheimer’s disease brains and skin fibroblasts. J Alzheimers Dis 2015; 43: 491-509.
[221]
Hongpaisan J, Sun MK, Alkon DL. PKC epsilon activation prevents synaptic loss, Abeta elevation, and cognitive deficits in Alzheimer’s disease transgenic mice. J Neurosci 2011; 31: 630-43.
[222]
Hongpaisan J, Xu C, Sen A, Nelson TJ, Alkon DL. PKC activation during training restores mushroom spine synapses and memory in the aged rat. Neurobiol Dis 2013; 55: 44-62.
[223]
Tan Z, Turner RC, Leon RL, et al. Bryostatin improves survival and reduces ischemic brain injury in aged rats after acute ischemic stroke. Stroke 2013; 44: 3490-7.
[224]
Sun MK, Hongpaisan J, Lim CS, Alkon DL. Bryostatin-1 restores hippocampal synapses and spatial learning and memory in adult fragile X mice. J Pharmacol Exp Ther 2014; 349: 393-401.
[225]
Burke WJ, Chung HD, Marshall GL, Gillespie KN, Joh TH. Evidence for decreased transport of PNMT protein in advanced Alzheimgr’s disease. JAGS 1990; 38: 1275-82.
[226]
Burke WJ, Chung HD, Nakra BR, Grossberg GT, Joh TH. Phenylethanolamine N-methyltransferase activity is decreased in Alzheimer’s disease brains. Ann Neurol 1987; 22: 278-80.
[227]
Mann MB, Wu S, Rostamkhani M, Tourtellotte W, McMarry J, Comings DE. Phenylethanolamine N-methyltransferase (PNMT) gene and early-onset Alzheimer disease. Am J Med Genet 2001; 105: 312-6.
[229]
Nixon RA. Calcium-activated neutral proteinases as regulators of cellular function: Implications for Alzheimer’s disease pathogenesis. Ann N Y Acad Sci 1988; 568: 198-206.
[230]
Saito KI, Elce JS, Hamos JE, Nixon RA. Widespread activation of calcium-activated neutral proteinase (calpain) in the brain in Alzheimer disease: A potential molecular basis for neuronal degeneration. Proc Natl Acad Sci USA 1993; 90: 2628-32.
[231]
Bhattacharyya R, Kovacs DM. ACAT inhibition and amyloid beta reduction. Biochim Biophys Acta 2010; 1801: 960-5.
[232]
Schreurs BG. The effects of cholesterol on learning and memory. Neurosci Biobehav Rev 2010; 34: 1366-79.
[233]
Chang CC, Sun J, Chang TY. Membrane-bound O-acyltransferases (MBOATs). Front Biol 2011; 6: 177-82.
[234]
Chang TY, Li BL, Chang CC, Urano Y. Acyl-coenzyme A: cholesterol acyltransferases. Am J Physiol Endocrinol Metab 2009; 297: E1-9.
[235]
Chan RB, Oliveira TG, Cortes EP, et al. Comparative lipidomic analysis of mouse and human brain with Alzheimer disease. J Biol Chem 2012; 287: 2678-88.
[236]
Tajima Y, Ishikawa M, Maekawa K, et al. Lipidomic analysis of brain tissues and plasma in a mouse model expressing mutated human amyloid precursor protein/tau for Alzheimer’s disease. Lipids Health Dis 2013; 12: 68.
[237]
Puglielli L, Konopka G, Pack-Chung E, et al. Acyl-coenzyme A: cholesterol acyltransferase modulates the generation of the amyloid beta-peptide. Nat Cell Biol 2001; 3: 905-12.
[238]
Hutter-Paier B, Huttunen HJ, Puglielli L. The ACAT inhibitor CP-113,818 markedly reduces amyloid pathology in a mouse model of Alzheimer’s disease. Neuron 2004; 44: 227-38.
[239]
Shibuya Y, Niu Z, Bryleva EY, et al. Acyl-coenzyme A: cholesterol acyltransferase 1 blockage enhances autophagy in the neurons of triple transgenic Alzheimer’s disease mouse and reduces human P301L-tau content at the presymptomatic stage. Neurobiol Aging 2005; 36: 2248-59. a
[240]
Shibuya Y, Chang CC, Chang TY. ACAT1/SOAT1 as a therapeutic target for Alzheimer’s disease. Future Med Chem 2015; 7: 2451-67. b
[241]
Schenk B, Fernandez F, Waechter CJ. The inside and outside of dolichyl phosphate biosynthesis and recycling in the endoplasmic reticulum. Glycobiology 2001; 11: 61R-70R.
[242]
Volpe JJ, Sakakihara Y, Rust RS. Dolichol kinase and the regulation of dolichyl phosphate levels in developing brain. Brain Res 1987; 428: 193-200.
[243]
Schedin-Weiss S, Winblad B, Tjernberg LO. The role of protein glycosylation in Alzheimer disease. FEBS 2013; 281: 46-62.
[244]
Ren L, Xi Ren . Meta-analyses of four polymorphisms of lipoprotein lipase associated with the risk of Alzheimer’s disease. Neurosci Lett 2016; 619: 73-8.
[245]
Wang H, Eckel RH. Lipoprotein lipase in the brain and nervous system. Annu Rev Nutr 2012; 32: 147-60.
[246]
Rebeck GW, Steven D, Harr BA, et al. Multiple, diverse senile plaque-associated proteins are ligands of an apolipoprotein E receptor, the α2-macroglobulin receptor/low-density lipoprotein receptor-related protein. Ann Neurol 1995; 37: 211-7.
[247]
Nishitsuji K, Hosono T, Uchimura K, Michikawa M. Lipoprotein Lipase is a novel amyloid-β (aβ)-binding protein that promotes glycosaminoglycan-dependent cellular uptake of aβ in astrocytes. J Biol Chem 2010; 286: 6393-401.
[248]
Gong H, Dong W, Rostad SW, et al. Lipoprotein lipase (lpl) is associated with neurite pathology and its levels are markedly reduced in the dentate gyrus of alzheimer’s disease brains. J Histochem Cytochem 2013; 61: 857-68.
[249]
Yu Tian , Taussig MD, DiPatrizio NV, et al. Deficiency of lipoprotein lipase in neurons decreases ampa receptor phosphorylation and leads to neurobehavioral abnormalities in Mice. PLoS One 2015; 10: e0135113.
[250]
Cai Z, Yan LJ, Li Keshen , Quazi SH, Zhao B. Roles of amp-activated protein kinase in Alzheimer’s disease. Neuromolecular Med 2012; 14: 1-14.
[251]
Zhang BB, Zhou G, Li C. AMPK: an emerging drug target for diabetes and the metabolic syndrome. Cell Metab 2009; 9: 407-16.
[252]
Seixas da Silva GS, Melo HM, Lourenco MV, et al. Amyloid-β oligomers transiently inhibit AMP-activated kinase and cause metabolic defects in hippocampal neurons. J Biol Chem 2017; 292: 7395-406.
[253]
Domise M, Didier S, Marinangeli C, et al. AMP-activated protein kinase modulates tau phosphorylation and tau pathology in vivo. Sci Rep 2016; 6: 26758.
[254]
Block ML. NADPH oxidase as a therapeutic target in Alzheimer’s disease. BMC Neurosci 2008; 9: S8.
[255]
Abeti R, Abramov AY, Duchen MR. β-amyloid activates PARP causing astrocytic metabolic failure and neuronal death. Brain 2011; 134: 1658-72.
[256]
Kamel D, Gray C, Walia JS, Kumar V. PARP inhibitor drugs in the treatment of breast, ovarian, prostate and pancreatic cancers: an update of clinical trials. Curr Drug Targets 2018; 19: 21-37.
[257]
Abramov AY, Duchen MR. Mechanisms underlying the loss of mitochondrial membrane potential in glutamate excitotoxicity. Biochim Biophys Acta 2008; 1777: 953-64.
[258]
Martire S, Mosca L, d’Erme M. PARP-1 involvement in neurodegeneration: A focus on Alzheimer’s and Parkinson’s diseases. Mech Ageing Dev 2015; 146: 53-64.
[259]
García-Osta A, Tejedor M, Barroso C, Oyarzábal J, Franco F. Phosphodiesterases as therapeutic targets for alzheimer’s disease. ACS Chem Neurosci 2012; 3: 832-44.
[260]
Lakics V, Karran EH, Boess FG. Quantitative comparison of phosphodiesterase mRNA distribution in human brain and peripheral tissues. Neuropharmacology 2010; 59: 367-74.
[261]
Deshmukh R, Sharma V, Mehan S, Sharma N, Bedi KL. Amelioration of intracerebroventricular streptozotocin induced cognitive dysfunction and oxidative stress by vinpocetine- a PDE1 inhibitor. Eur J Pharmacol 2009; 620: 49-56.
[262]
Rodefer JS, Saland SK, Eckrich SJ. Selective phosphodiesterase inhibitors improve performance on the ED/ID cognitive task in rats. Neuropharmacology 2012; 62: 1182-90.
[263]
Rose GM, Hopper A, De Vivo M, Tehim A. Phosphodiesterase inhibitors for cognitive enhancement. Curr Pharm Des 2005; 11: 3329-34.
[264]
Puzzo D, Staniszewski A, Deng S, et al. phosphodiesterase-5 inhibition improves synaptic function, memory, and amyloid-β load in an Alzheimer’s disease mouse model. J Neurosci 2009; 29: 8075-86.
[265]
Palmeri A, Privitera L, Giunta S, Loreto C, Puzzo D. Inhibition of phosphodiesterase-5 rescues age related impairment of synaptic plasticity and memory. Behav Brain Res 2013; 240: 11-20.
[266]
Paterniti I, Mazzon E, Gil C, et al. PDE 7 inhibitors: new potential drugs for the therapy of spinal cord injury. PLoS One 2011; 6: e15937.
[267]
Van der Staay FJ, Rutten K, Barfacker L, et al. The novel selective PDE9 inhibitor BAY 73-6691 improves learning and memory in rodents. Neuropharmacology 2008; 55: 908-18.
[268]
Rodefer JS, Murphy ER, Baxter MG. PDE10A inhibition reverses subchronic PCP-induced deficits in attentional setshifting in rats. Eur J Neurosci 2005; 21: 1070-6.
[269]
Hebb AL, Robertson HA, Denovan EM. Striatal phosphodiesterase mRNA and protein levels are reduced in Huntington’s disease transgenic mice prior to the onset of motor symptoms. Neuroscience 2004; 123: 967-81.
[270]
O’Connor V, Genin A, Davis S, et al. Differential amplification of intron-containing transcripts reveals long term potentiation-associated up-regulation of specific Pde10A phosphodiesterase splice variants. J Biol Chem 2004; 279: 15841-9.
[271]
Kelly MP, Logue SF, Brennan J, et al. Phosphodiesterase 11A in brain is enriched in ventral hippocampus and deletion causes psychiatric disease-related phenotypes. Proc Natl Acad Sci USA 2011; 107: 8457-62.
[272]
Li Y, et al. Phosphodiesterase-4D knockout and RNAi-mediated knockdown enhance memory and increase hippocampal neurogenesis via increased cAMP signaling. J Neurosci 2011; 31: 172-83.
[273]
Zhang C, et al. RNA interference-mediated knockdown of long-form phosphodiesterase-4d (PDE4D) enzyme reverses amyloid-β42-induced memory deficits in mice. J Alzheimers Dis 2014; 38: 269-80.
[274]
Chuang MD, Leng Y, Marinova Z, Kim HJ, Chiu CT. Multiple roles of HDAC inhibition in neurodegenerative conditions. Trends Neurosci 2009; 32: 591-601.
[275]
Mai A, Rotili D, Valente S, Kazantsev AG. Histone deacetylase inhibitors and neurodegenerative disorders: Holding the promise. Curr Pharm Des 2009; 15: 3940-57.
[276]
Voelter-Mahlknecht S, Ho AD, Mahlknecht U. Chromosomal organization and localization of the novel class IV human histone deacetylase 11 gene. Int J Mol Med 2005; 16: 589-98.
[277]
Schmaussa C. The roles of class I histone deacetylases (HDACs) in memory, learning, and executive cognitive functions: A review. Neurosci Biobehav Rev 2017; 83: 63-71.
[278]
Outeiro TF, Marques O, Kazantsev A. Therapeutic role of sirtuins in neurodegenerative disease. Biochim Biophys Acta 2008; 1782: 363-9.
[279]
Guan JS, Haggarty SJ, Giacometti E, et al. HDAC2 negatively regulates memory formation and synaptic plasticity. Nature 2009; 459: 55-60.
[280]
Kilgore M, Miller CA, Fass DM, et al. Inhibitors of class 1 histone deacetylases reverse contextual memory deficits in a mouse model of Alzheimer’s disease. Neuropsychopharmacology 2010; 35: 870-80.
[281]
Kim C, Choi H, Jung ES, et al. HDAC6 inhibitor blocks amyloid Beta-induced impairment of mitochondrial transport in hippocampal neurons. PLoS One 2012; 7: e42983.
[282]
Strehler EE. Plasma membrane Ca2+-ATPases: Targets of oxidative stress in brain aging and neurodegeneration. World J Biol Chem 2010; 26: 271-80.
[283]
Dawson TM, Dawson VL, Snyder SH. A novel neuronal messenger molecule in brain: The free radical, nitric oxide. Ann Neurol 1992; 32: 297-311.
[284]
Paudel HK, Lew J, Ali Z, Wang JH. Brain proline-directed protein kinase phosphorylates tau on sites that are abnormally phosphorylated in tau associated with Alzheimer’s paired helical filaments. J Biol Chem 1993; 268: 23512-8.
[285]
Ramsay RR. Molecular aspects of monoamine oxidase-B. Prog Neuropsychopharmacol Biol Psychiatry 2016; 1: 81-9.
[286]
Mata AM, Berrocal M, Sepulveda MR. Impairment of the activity of the plasma membrane Ca2+-ATPase in Alzheimer’s disease. Biochem Soc Trans 2011; 39: 819-22.
[287]
Allal B, Einar MS, Pavan KK. Tau as a therapeutic target for Alzheimer’s disease. Curr Alzheimer Res 2011; 8: 666-77.
[288]
Yan R, Fan Q, Zhou Z, Vassar R. Inhibiting BACE1 to reverse synaptic dysfunctions in Alzheimer’s disease. Neurosci Biobehav Rev 2016; 65: 326-40.
[289]
Jackson B, Brocker C, Thompson DC, et al. Update on the aldehyde dehydrogenase gene (ALDH) superfamily. Hum Genomics 2011; 5: 283-303.
[290]
Wood PL, Khan MA, Moskal JR. The concept of “aldehyde load” in neurodegenerative mechanisms: cytotoxicity of the polyamine degradation products hydrogen peroxide, acrolein, 3-aminopropanal, 3-acetamidopropanal and 4-aminobutanal in a retinal ganglion cell line. Brain Res 2007; 1145: 150-6.
[291]
Aldini G, Dalle-Donne I, Facino RM, Milzani A, Carini M. Intervention strategies to inhibit protein carbonylation by lipoxidation-derived reactive carbonyls. Med Res Rev 2007; 27: 817-68.
[292]
Lovell MA, Ehmann WD, Mattson MP, Markesbery WR. Elevated 4-hydroxynonenal in ventricular fluid in Alzheimer’s disease. Neurobiol Aging 1997; 18: 457-61.
[293]
Ishrat T, Hoda MN, Khan MB, Yousuf S. Amelioration of cognitive deficits and neurodegeneration by curcumin in rat model of sporadic dementia of Alzheimer’s type (SDAT). Eur Neuropsychopharmacol 2009; 19: 636-47.
[294]
Zarkovic K. 4-hydroxynonenal and neurodegenerative diseases. Mol Aspects Med 2003; 24: 293-303.
[295]
Mark RJ, Pang Z, Geddes JW, Uchida K, Mattson MP. Amyloid beta-peptide impairs glucose transport in hippocampal and cortical neurons: involvement of membrane lipid peroxidation. J Neurosci 1997; 17: 1046-54.
[296]
Marchitti SA, Deitrich RA, Vasiliou V. Neurotoxicity and metabolism of the catecholamine-derived 3,4-dihydroxyphenylacetalde- hyde and 3,4-dihydroxyphenylglycolaldehyde: the role of aldehyde dehydrogenase. Pharmacol Rev 2007; 59: 125-50.
[297]
D’Souza Y, Elharram A, Soon-Shiong R, Andrew RD, Bennett BM. Characterization of Aldh2-/- mice as an age-related model of cognitive impairment and Alzheimer’s disease. Mol Brain 2015; 8: 1-16.
[298]
Bai J, Mei Y. Overexpression of aldehyde dehydrogenase-2 attenuates neurotoxicity induced by 4-hydroxynonenal in cultured primary hippocampal neurons. Neurotox Res 2011; 19: 412-22.
[299]
Ohsawa I, Nishimaki K, Yasuda C, Kamino K, Ohta S. Deficiency in a mitochondrial aldehyde dehydrogenase increases vulnerability to oxidative stress in PC12 cells. J Neurochem 2003; 84: 1110-7.
[300]
Michel TM, Gsell W, Kasbauer L, et al. Increased Mitochondrial Aldehydedehydrogenase in the putamen of individuals with Alzheimer’s disease. J Alzheimers Dis 2010; 19: 1295-301.
[301]
Grunblatt E, Riederer P. Aldehyde dehydrogenase (ALDH) in Alzheimer’s and Parkinson’s disease. J Neural Transm (Vienna) 2014; 123: 83-90.
[302]
Kanamaru T, Kamimura N, Yokota T, et al. Oxidative stress accelerates amyloid deposition and memory impairment in a double-transgenic mouse model of Alzheimer’s disease. Neurosci Lett 2015; 587: 126-31.
[303]
Li M, Zhang P, Wei HJ, et al. Hydrogen sulfide ameliorates homocysteine-induced cognitive dysfunction by inhibition of reactive aldehydes involving upregulation of ALDH2. Int J Neuropsychopharmacol 2017; 20: 305-15.
[304]
Seshadri S, Beiser A, Selhub J, et al. Plasma homocysteine as a risk factor for dementia and Alzheimer’s disease. N Engl J Med 2002; 346: 476-83.
[305]
Schimidt R, Neff F, Lampl C, et al. Therapy of Alzheimer’s disease: current status and future development. Neuropsychiatrie (Deisenhof) 2008; 22: 153-71.
[306]
Grill JD, Cummings JL. Current therapeutic targets for the treatment of Alzheimer’s disease. Expert Rev Neurother 2010; 10: 711-28.
[307]
Horrobin DF, Bennett CN. phospholipid metabolism and the pathophysiology of psychiatry and neurological disorders. In: Peet M., Glen I., Horrobin D.F. Phospholipid Spectrum Disorders in Psychiatry and Neurology. 2nd ed. Lancashire UK: Marius Press 2003.
[308]
Dennis EA, Cao J, Hsu YH, Magrioti V, Kokotos G. Phospholipase A2 enzymes: physical structure, biological function, disease implication, chemical inhibition, and therapeutic intervention. Chem Rev 2011; 111: 6130-85.
[309]
Polverino A, Grimaldi M, Sorrentino P, Jacini F, Maria D’Ursi A, Sorrentino G. Effects of Acetylcholine on β-Amyloid-Induced cPLA2 Activation in the TB Neuroectodermal Cell Line: Implications for the Pathogenesis of Alzheimer’s Disease. Cell Mol Neurobiol 2017.
[http://dx.doi.org/10.1007/s10571-017-0555-4]
[http://dx.doi.org/10.1007/s10571-017-0555-4]
[310]
Lambeau G, Gelb MH. Biochemistry and physiology of mammalian secreted phospholipases A2. Annu Rev Biochem 2008; 77: 495-520.
[311]
Gattaz WE, Cairns NJ, Levy R, Forstl H, Braus DE, Maras A. Decreased phospholipase A2 activity in the brain and in platelets of patients with Alzheimer’s disease. Eur Arch Psychiatry Clin Neurosci 1996; 246: 129-31.
[312]
Gattaz WF, Maras A, Cairns NJ, Levy R, Forstl H. Decreased Phospholipase A2 Activity in Alzheimer Brains. Soc Biol Psychiatry 1995; 37: 13-7.
[313]
Mury FB, da Silva WC, Barbosa NR, et al. Lithium activates brain phospholipase A2 and improves memory in rats: implications for Alzheimer’s disease. Eur Arch Psychiatry Clin Neurosci 2015; 266: 607-18.
[314]
Stephenson DT, Lemere CA, Selkoe DJ, Clemens JA. Cytosolic Phospholipase A2 (cPLA2) Immunoreactivity Is Elevated in Alzheimer’s Disease Brain. Neurobiol Dis 1996; 3: 51-63.
[315]
Sanchez-Mejia RO, Newman JW, et al. Phospholipase A2 reduction ameliorates cognitive deficits in a mouse model of Alzheimer’s disease. Nat Neurosci 2008; 11: 1311-8.
[316]
Gentile MT, Reccia MG, Sorrentino PP, et al. Role of Cytosolic Calcium-Dependent Phospholipase A2 in Alzheimer’s Disease Pathogenesis. Mol Neurobiol 2012; 45: 596-604.
[317]
Costa AC, Joaquim HP, Forlenza O, Talib LL, Gattaz WF. Plasma lipids metabolism in mild cognitive impairment and Alzheimer’s disease. World J Biol Psychiatry 2017; 19: 1-17.
[318]
Garcia AM, et al. PLA2G3, a Gene Involved in Oxidative Stress Induced Death, is Associated with Alzheimer’s Disease. J Alzheimers Dis 2010; 22: 1181-7.
[319]
Rapoport SI. Brain arachidonic and docosahexaenoic acid cascades are selectively altered by drugs, diet and disease. Prostaglandins Leukot Essent Fatty Acids 2008; 79: 153-6.
[320]
Phillis JW, Horrocks LA, Farooqui AA. Cyclooxygenases, lipoxygenases, and epoxygenases in CNS: their role and involvement in neurological disorders. Brain Res Brain Res Rev 2006; 52: 201-43.
[321]
Pasinetti GM. From epidemiology to therapeutic trials with antiinflammatory drugs in Alzheimer’s disease: The role of NSAIDs and cyclooxygenase in beta-amyloidosis and clinical dementia. J Alzheimers Dis 2002; 4: 435-45.
[322]
Kalra J, Kumar P, Majeed AB, Prakash A. Modulation of LOX and COX pathways via inhibition of amyloidogenesis contributes to mitoprotection against β-amyloid oligomer-induced toxicity in an animal model of Alzheimer’s disease in rats. Pharmacol Biochem Behav 2016; 146-147: 1-12.
[323]
Bitto A, Giuliani D, Pallio G, et al. Effects of COX1-2/5-LOX blockade in Alzheimer transgenic 3xTgAD mice. Inflamm Res 2017; 66: 389-98.
[324]
Schmitt B, Bernhardt T, Moeller HJ, Heuser I, Frölich L. Combination therapy in Alzheimer’s disease: A review of current evidence. CNS Drugs 2004; 18: 827-44.
[325]
Mani V, Jaafar SM, Mohd Azahan NS, et al. Ciproxifan improves cholinergic transmission, attenuates neuroinflammation and oxidative stress but does not reduce amyloid level in transgenic mice. Life Sci 2017; 180: 23-35.
[326]
Wolfe MS. ץ-Secretase inhibitors and modulators for Alzheimer’s disease. J Neurochem 2012; 120: 89-98.
[327]
Hiltunen M, Iivonen S, Soininen H. Aromatase enzyme and Alzheimer’s disease. Minerva Endocrinol 2006; 31: 61-73.
Article Metrics
71
5