Review

Molecular Biomarkers for Diagnosis & Therapies of Alzheimer’s Disease

  • Received: 26 August 2016 Accepted: 26 October 2016 Published: 02 November 2016
  • Alzheimer’s disease (AD) has been discovered before the century but scientists still have not found the way to cure the disease. The basic requirement for successful cure requires the early diagnosis of the disease. Presence of Aβ42, total tau protein and phosphorylated tau have been used in the earlier days but these diagnostic markers fail the detection in the initial stages. Hence the need of the hour is to identify the various biomarkers which can be detected in the earlier stages of AD. Impaired cellular signaling is common in all the diseases and identification of particular signaling pathway helps in the identification of biomarker. Important signaling pathways such as Akt, FAS/NO, MAPK, Ca2+ are found to be altered in the AD brain. Protein molecules upstream or downstream to these signaling molecules can be potential molecular markers in the diagnosis of AD. This review comprises molecular markers which are crucial in the AD and play a significant role by altering the signaling pathways. These biomarkers will not only help in the understanding of pathobiology of AD but also provide an insight for the researchers working in the direction of AD biomarker discovery and drug discovery.

    Citation: Pravin D Potdar, Aashutosh U Shetti. Molecular Biomarkers for Diagnosis & Therapies of Alzheimer’s Disease[J]. AIMS Neuroscience, 2016, 3(4): 433-453. doi: 10.3934/Neuroscience.2016.4.433

    Related Papers:

  • Alzheimer’s disease (AD) has been discovered before the century but scientists still have not found the way to cure the disease. The basic requirement for successful cure requires the early diagnosis of the disease. Presence of Aβ42, total tau protein and phosphorylated tau have been used in the earlier days but these diagnostic markers fail the detection in the initial stages. Hence the need of the hour is to identify the various biomarkers which can be detected in the earlier stages of AD. Impaired cellular signaling is common in all the diseases and identification of particular signaling pathway helps in the identification of biomarker. Important signaling pathways such as Akt, FAS/NO, MAPK, Ca2+ are found to be altered in the AD brain. Protein molecules upstream or downstream to these signaling molecules can be potential molecular markers in the diagnosis of AD. This review comprises molecular markers which are crucial in the AD and play a significant role by altering the signaling pathways. These biomarkers will not only help in the understanding of pathobiology of AD but also provide an insight for the researchers working in the direction of AD biomarker discovery and drug discovery.


    加载中
    [1] Butterfield D, Castegna A, Lauderback C, et al. (2002) Evidence that amyloid beta-peptide-induced lipid peroxidation and its sequelae in Alzheimer’s disease brain contribute to neuronal death. Neurobiol Aging 23: 655-664. doi:10.1016/S0197-4580(01)00340-2. doi: 10.1016/S0197-4580(01)00340-2
    [2] Ramsden M, Kotilinek L, Forster C, et al. (2005) Age-dependent neurofibrillary tangle formation, neuron loss, and memory impairment in a mouse model of human tauopathy (P301L). J Neurosci 25: 10637-10647. doi:10.1523/JNEUROSCI.3279-05.2005. doi: 10.1523/JNEUROSCI.3279-05.2005
    [3] Serpell LC (2000) Alzheimer’s amyloid fibrils: structure and assembly. Biochim Biophys Acta- Mol Basis Dis 1502: 16-30. doi:10.1016/S0925-4439(00)00029-6. doi: 10.1016/S0925-4439(00)00029-6
    [4] Nunan J, Small DH (2000) Regulation of APP cleavage by α-, β- and γ-secretases. FEBS Lett 483: 6-10. doi:10.1016/S0014-5793(00)02076-7. doi: 10.1016/S0014-5793(00)02076-7
    [5] Chasseigneaux S, Allinquant B (2012) Functions of Aβ, sAPPα and sAPPβ : similarities and differences. J Neurochem 120 Suppl: 99-108. doi:10.1111/j.1471-4159.2011.07584.x.
    [6] Sadik G, Kaji H, Takeda K, et al. (1999) In vitro processing of amyloid precursor protein by cathepsin D. Int J Biochem Cell Biol 31: 1327-1337. http://www.ncbi.nlm.nih.gov/pubmed/10605825. Accessed January 3, 2016. doi: 10.1016/S1357-2725(99)00053-9
    [7] Kume H, Maruyama K, Kametani F (2004) Intracellular domain generation of amyloid precursor protein by epsilon-cleavage depends on C-terminal fragment by alpha-secretase cleavage. Int J Mol Med 13: 121-125. http://www.ncbi.nlm.nih.gov/pubmed/14654982.
    [8] Konietzko U (2012) AICD nuclear signaling and its possible contribution to Alzheimer’s disease. Curr Alzheimer Res 9: 200-216. http://www.ncbi.nlm.nih.gov/pubmed/21605035. doi: 10.2174/156720512799361673
    [9] Brion JP, Couck AM, Passareiro E, et al. (1985) Neurofibrillary tangles of Alzheimer’s disease: an immunohistochemical study. J Submicrosc Cytol 17: 89-96. http://europepmc.org/abstract/med/3973960.
    [10] Ferrer I, Gomez-Isla T, Puig B, et al. (2005) Current advances on different kinases involved in tau phosphorylation, and implications in Alzheimer’s disease and tauopathies. Curr Alzheimer Res 2: 3-18. http://www.ncbi.nlm.nih.gov/pubmed/15977985. doi: 10.2174/1567205052772713
    [11] Williams DR (2006) Tauopathies: classification and clinical update on neurodegenerative diseases associated with microtubule-associated protein tau. Intern Med J 36: 652-660. doi:10.1111/j.1445-5994.2006.01153.x. doi: 10.1111/j.1445-5994.2006.01153.x
    [12] Levy-Lahad E, Wasco W, Poorkaj P, et al. (1995) Candidate gene for the chromosome 1 familial Alzheimer’s disease locus. Science 269: 973-977. doi:10.1126/science.7638622. doi: 10.1126/science.7638622
    [13] Bertram L, Blacker D, Mullin K, et al. (2000) Evidence for genetic linkage of Alzheimer’s disease to chromosome 10q. Science 290: 2302-2303. doi:10.1126/science.290.5500.2302. doi: 10.1126/science.290.5500.2302
    [14] Beecham GW, Martin ER, Li Y-J, et al. (2008) Genome-wide association study implicates a chromosome 12 risk locus for late-onset Alzheimer disease. Am J Hum Genet 84: 35-43. doi:10.1016/j.ajhg.2008.12.008.
    [15] Wilkins CH, Sheline YI, Roe CM, et al. (2006) Vitamin D deficiency is associated with low mood and worse cognitive performance in older adults. Am J Geriatr Psychiatry 14: 1032-1040. doi:10.1097/01.JGP.0000240986.74642.7c. doi: 10.1097/01.JGP.0000240986.74642.7c
    [16] Mullan M, Houlden H, Windelspecht M, et al. (1992) A locus for familial early-onset Alzheimer’s disease on the long arm of chromosome 14, proximal to the alpha 1-antichymotrypsin gene. Nat Genet 2: 340-342. doi:10.1038/ng1292-340. doi: 10.1038/ng1292-340
    [17] St George-Hyslop P, Haines J, Rogaev E, et al. (1992) Genetic evidence for a novel familial Alzheimer’s disease locus on chromosome 14. Nat Genet 2: 330-334. doi:10.1038/ng1292-330. doi: 10.1038/ng1292-330
    [18] Pericak-Vance M a, Bebout JL, Gaskell PC, et al. (1991) Linkage studies in familial Alzheimer disease: evidence for chromosome 19 linkage. Am J Hum Genet 48: 1034-1050. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1683100/pdf/ajhg00090-0019.pdf.
    [19] Chartier-Harlin MC, Parfitt M, Legrain S, et al. (1994) Apolipoprotein E, epsilon 4 allele as a major risk factor for sporadic early and late-onset forms of Alzheimer’s disease: analysis of the 19q13.2 chromosomal region. Hum Mol Genet 3: 569-574. doi:10.1093/hmg/3.4.569. doi: 10.1093/hmg/3.4.569
    [20] Yu J-T, Tan L, Hardy J (2014) Apolipoprotein E in Alzheimer’s disease: an update. Annu Rev Neurosci 37: 79-100. doi:10.1146/annurev-neuro-071013-014300. doi: 10.1146/annurev-neuro-071013-014300
    [21] Strittmatter WJ, Weisgraber KH, Goedert M, et al. (1994) Hypothesis: microtubule instability and paired helical filament formation in the Alzheimer disease brain are related to apolipoprotein E genotype. Exp Neurol 125: 163-171. doi:S0014488684710193. doi: 10.1006/exnr.1994.1019
    [22] Wu L, Rosa-Neto P, Hsiung G-YR, et al. (2012) Early-onset familial Alzheimer’s disease (EOFAD). Can J Neurol Sci 39: 436-445. doi:W4438L6488727555. doi: 10.1017/S0317167100013949
    [23] Olsson A, Vanderstichele H, Andreasen N, et al. (2005) Simultaneous measurement of β-amyloid (1-42), total Tau, and phosphorylated Tau (Thr181) in cerebrospinal fluid by the xMAP technology. Clin Chem 51: 336-345. doi:10.1373/clinchem.2004.039347. doi: 10.1373/clinchem.2004.039347
    [24] Petraki CD, Karavana VN, Skoufogiannis PT, et al. (2001) The spectrum of human kallikrein 6 (zyme/protease M/neurosin) expression in human tissues as assessed by immunohistochemistry. J Histochem Cytochem 49: 1431-1441. http://www.ncbi.nlm.nih.gov/pubmed/11668196. doi: 10.1177/002215540104901111
    [25] Rockenstein E, Nuber S, Overk CR, et al. (2014) Accumulation of oligomer-prone α-synuclein exacerbates synaptic and neuronal degeneration in vivo. Brain 137: 1496-1513. doi:10.1093/brain/awu057. doi: 10.1093/brain/awu057
    [26] Spencer B, Valera E, Rockenstein E, et al. (2015) A brain-targeted, modified neurosin (kallikrein-6) reduces α-synuclein accumulation in a mouse model of multiple system atrophy. Mol Neurodegener 10: 48. doi:10.1186/s13024-015-0043-6. doi: 10.1186/s13024-015-0043-6
    [27] Ogawa K, Yamada T, Tsujioka Y, et al. (2000) Localization of a novel type trypsin-like serine protease, neurosin, in brain tissues of Alzheimer’s disease and Parkinson's disease. Psychiatry Clin Neurosci 54: 419-426. doi:10.1046/j.1440-1819.2000.00731.x. doi: 10.1046/j.1440-1819.2000.00731.x
    [28] Diamandis EP, Yousef GM, Petraki C, et al. (2000). Human kallikrein 6 as a biomarker of alzheimer’s disease. Clin Biochem 33:663-667. http://www.ncbi.nlm.nih.gov/pubmed/11166014. doi: 10.1016/S0009-9120(00)00185-5
    [29] Saper CB, Scammell TE, Lu J (2005) Hypothalamic regulation of sleep and circadian rhythms. Nature 437: 1257-1263. doi:10.1038/nature04284. doi: 10.1038/nature04284
    [30] de Lecea L, Kilduff TS, Peyron C, et al. (1998) The hypocretins: Hypothalamus-specific peptides with neuroexcitatory activity. Proc Natl Acad Sci 95: 322-327. doi:10.1073/pnas.95.1.322. doi: 10.1073/pnas.95.1.322
    [31] Liguori C, Romigi A, Nuccetelli M, et al. (2014) Orexinergic System Dysregulation, Sleep Impairment, and Cognitive Decline in Alzheimer Disease. JAMA Neurol 71: 1498-1505. doi:10.1001/jamaneurol.2014.2510. doi: 10.1001/jamaneurol.2014.2510
    [32] Baumann CR, Hersberger M, Bassetti CL (2006) Hypocretin-1 (orexin A) levels are normal in Huntington’s disease. J Neurol 253: 1232-1233. doi:10.1007/s00415-006-0146-7. doi: 10.1007/s00415-006-0146-7
    [33] Dauvilliers YA, Lehmann S, Jaussent I, et al. (2014). Hypocretin and brain β-amyloid peptide interactions in cognitive disorders and narcolepsy. Front Aging Neurosci 6. doi:10.3389/fnagi.2014.00119.
    [34] Friedman LF, Zeitzer JM, Lin L, et al. et al. (2007) In Alzheimer disease, increased wake fragmentation found in those with lower hypocretin-1. Neurology 68: 793-794. doi:10.1212/01.wnl.0000256731.57544.f9. doi: 10.1212/01.wnl.0000256731.57544.f9
    [35] Slats D, Claassen JAHR, Lammers GJ, et al. (2012) Association between hypocretin-1 and amyloid-β42 cerebrospinal fluid levels in Alzheimer’s disease and healthy controls. Curr Alzheimer Res 9: 1119-1125. http://www.ncbi.nlm.nih.gov/pubmed/22742854. doi: 10.2174/156720512804142840
    [36] Fronczek R, van Geest S, Frölich M, et al. (2012) Hypocretin (orexin) loss in Alzheimer’s disease. Neurobiol Aging 33: 1642-1650. doi:10.1016/j.neurobiolaging.2011.03.014. doi: 10.1016/j.neurobiolaging.2011.03.014
    [37] Gallone S, Boschi S, Rubino E, et al. et al. (2014) Is HCRTR2 a genetic risk factor for Alzheimer’s disease? Dement Geriatr Cogn Disord 38: 245-253. doi:10.1159/000359964. doi: 10.1159/000359964
    [38] Tucker HM, Kihiko M, Caldwell JN, et al. (2000) The plasmin system is induced by and degrades amyloid-beta aggregates. J Neurosci 20: 3937-3946. doi:20/11/3937.
    [39] Man H-Y, Ma X-M (2012) A role for neuroserpin in neuron morphological development. J Neurochem 121: 495-496. doi:10.1111/j.1471-4159.2012.07655.x. doi: 10.1111/j.1471-4159.2012.07655.x
    [40] Ledesma MD, Da Silva JS, Crassaerts K, et al. (2000) Brain plasmin enhances APP alpha-cleavage and Abeta degradation and is reduced in Alzheimer’s disease brains. EMBO Rep 1: 530-535. doi:10.1093/embo-reports/kvd107. doi: 10.1093/embo-reports/kvd107
    [41] Hanzel CE, Iulita MF, Eyjolfsdottir H, et al. (2014) Analysis of matrix metallo-proteases and the plasminogen system in mild cognitive impairment and Alzheimer’s disease cerebrospinal fluid. J Alzheimers Dis 40: 667-678. doi:10.3233/JAD-132282.
    [42] Kinghorn KJ, Crowther DC, Sharp LK, et al. (2006) Neuroserpin binds Abeta and is a neuroprotective component of amyloid plaques in Alzheimer disease. J Biol Chem 281: 29268-29277. doi:10.1074/jbc.M600690200. doi: 10.1074/jbc.M600690200
    [43] Fabbro S, Schaller K, Seeds NW (2011) Amyloid-beta levels are significantly reduced and spatial memory defects are rescued in a novel neuroserpin-deficient Alzheimer’s disease transgenic mouse model. J Neurochem 118: 928-938. doi:10.1111/j.1471-4159.2011.07359.x. doi: 10.1111/j.1471-4159.2011.07359.x
    [44] Subhadra B, Schaller K, Seeds NW (2013) Neuroserpin up-regulation in the Alzheimer’s disease brain is associated with elevated thyroid hormone receptor-β1 and HuD expression. Neurochem Int 63: 476-481. doi:10.1016/j.neuint.2013.08.010. doi: 10.1016/j.neuint.2013.08.010
    [45] Okada T, Kajimoto T, Jahangeer S, et al. (2009) Sphingosine kinase/sphingosine 1-phosphate signalling in central nervous system. Cell Signal 21: 7-13. doi:10.1016/j.cellsig.2008.07.011. doi: 10.1016/j.cellsig.2008.07.011
    [46] Cieślik M, Czapski GA, Strosznajder JB (2015) The Molecular Mechanism of Amyloid β42 Peptide Toxicity: The Role of Sphingosine Kinase-1 and Mitochondrial Sirtuins. PLoS One 10: e0137193. doi:10.1371/journal.pone.0137193. doi: 10.1371/journal.pone.0137193
    [47] Carro E, Trejo JL, Gomez-Isla T, et al. (2002) Serum insulin-like growth factor I regulates brain amyloid-beta levels. Nat Med 8: 1390-1397. doi:10.1038/nm793. doi: 10.1038/nm1202-793
    [48] Mizugishi K, Yamashita T, Olivera A, et al. (2005) Essential role for sphingosine kinases in neural and vascular development. Mol Cell Biol 2511113-11121. doi:10.1128/MCB.25.24.11113-11121.2005.
    [49] Couttas T a, Kain N, Daniels B, et al. (2014) Loss of the neuroprotective factor Sphingosine 1-phosphate early in Alzheimer’s disease pathogenesis. Acta Neuropathol Commun 2: 9. doi:10.1186/2051-5960-2-9. doi: 10.1186/2051-5960-2-9
    [50] Sivasubramanian M, Kanagaraj N, Dheen ST, et al. (2015) Sphingosine kinase 2 and sphingosine-1-phosphate promotes mitochondrial function in dopaminergic neurons of mouse model of Parkinson’s disease and in MPP+-treated MN9D cells in vitro. Neuroscience 290: 636-648. doi:10.1016/j.neuroscience.2015.01.032. doi: 10.1016/j.neuroscience.2015.01.032
    [51] Takasugi N, Sasaki T, Suzuki K, et al. (2011) BACE1 activity is modulated by cell-associated sphingosine-1-phosphate. J Neurosci 31: 6850-6857. doi:10.1523/JNEUROSCI.6467-10. doi: 10.1523/JNEUROSCI.6467-10.2011
    [52] Hagen N, Hans M, Hartmann D, et al. (2011) Sphingosine-1-phosphate links glycosphingolipid metabolism to neurodegeneration via a calpain-mediated mechanism. Cell Death Differ 18: 1356-1365. doi:10.1038/cdd.2011.7. doi: 10.1038/cdd.2011.7
    [53] Huh CG, Håkansson K, Nathanson CM, et al. (1999) Decreased metastatic spread in mice homozygous for a null allele of the cystatin C protease inhibitor gene. Mol Pathol 52: 332-340. http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=395718&tool=pmcentrez&rendertype=abstract. doi: 10.1136/mp.52.6.332
    [54] Wilson ME, Boumaza I, Lacomis D, et al. (2010) Cystatin C: a candidate biomarker for amyotrophic lateral sclerosis. PLoS One 5: e15133. doi:10.1371/journal.pone.0015133. doi: 10.1371/journal.pone.0015133
    [55] Simonsen AH, McGuire J, Podust VN, et al. (2007) A novel panel of cerebrospinal fluid biomarkers for the differential diagnosis of Alzheimer’s disease versus normal aging and frontotemporal dementia. Dement Geriatr Cogn Disord 24: 434-440. doi:10.1159/000110576. doi: 10.1159/000110576
    [56] Chen J, Liu C (2014) Association Of Serum Cystatin C Levels On The Progression And Cognition In Parkinson’s Disease (P4.045). Neurology 82: 45.
    [57] Chuo L-J, Sheu WHH, Pai M-C, et al. (2007) Genotype and plasma concentration of cystatin C in patients with late-onset Alzheimer disease. Dement Geriatr Cogn Disord 23: 251-257. doi:10.1159/000100021. doi: 10.1159/000100021
    [58] Crawford FC, Freeman MJ, Schinka JA, et al. (2000) A polymorphism in the cystatin C gene is a novel risk factor for late-onset Alzheimer’s disease. Neurology 55: 763-768. http://www.ncbi.nlm.nih.gov/pubmed/10993992. doi: 10.1212/WNL.55.6.763
    [59] Ghidoni R, Paterlini A, Albertini V, et al. (2011) Cystatin C is released in association with exosomes: a new tool of neuronal communication which is unbalanced in Alzheimer’s disease. Neurobiol Aging 32: 1435-1442. doi:10.1016/j.neurobiolaging.2009.08.013. doi: 10.1016/j.neurobiolaging.2009.08.013
    [60] Afonso S, Romagnano L, Babiarz B (2016) The expression and function of cystatin C and cathepsin B and cathepsin L during mouse embryo implantation and placentation. Development 124: 3415-3425. http://www.ncbi.nlm.nih.gov/pubmed/9310336.
    [61] Sastre M, Calero M, Pawlik M, et al. (2004) Binding of cystatin C to Alzheimer’s amyloid beta inhibits in vitro amyloid fibril formation. Neurobiol Aging 25: 1033-1043. doi:10.1016/j.neurobiolaging.2003.11.006. doi: 10.1016/j.neurobiolaging.2003.11.006
    [62] Maruyama K, Ikeda S, Ishihara T, et al. (1990) Immunohistochemical characterization of cerebrovascular amyloid in 46 autopsied cases using antibodies to beta protein and cystatin C. Stroke 21: 397-403. doi:10.1161/01.STR.21.3.397. doi: 10.1161/01.STR.21.3.397
    [63] Deng A, Irizarry MC, Nitsch RM, et al. (2001). Elevation of cystatin C in susceptible neurons in Alzheimer’s disease. Am J Pathol 159: 1061-1068. doi:10.1016/S0002-9440(10)61781-6. doi: 10.1016/S0002-9440(10)61781-6
    [64] Ponomareva OY, Holmen IC, Sperry AJ, et al. (2014) Calsyntenin-1 regulates axon branching and endosomal trafficking during sensory neuron development in vivo. J Neurosci 34: 9235-9248. doi:10.1523/JNEUROSCI.0561-14.2014. doi: 10.1523/JNEUROSCI.0561-14.2014
    [65] Vagnoni A, Perkinton MS, Gray EH, et al. (2012) Calsyntenin-1 mediates axonal transport of the amyloid precursor protein and regulates Aβ production. Hum Mol Genet 21: 2845-2854. doi:10.1093/hmg/dds109. doi: 10.1093/hmg/dds109
    [66] Yin GN, Lee HW, Cho J-Y, et al. (2009) Neuronal pentraxin receptor in cerebrospinal fluid as a potential biomarker for neurodegenerative diseases. Brain Res 1265: 158-170. doi:10.1016/j.brainres.2009.01.058. doi: 10.1016/j.brainres.2009.01.058
    [67] Ludwig A, Blume J, Diep T-M, et al. (2009) Calsyntenins mediate TGN exit of APP in a kinesin-1-dependent manner. Traffic 10: 572-589. doi:10.1111/j.1600-0854.2009.00886.x. doi: 10.1111/j.1600-0854.2009.00886.x
    [68] Pettem KL, Yokomaku D, Luo L, et al. (2013) The specific α-neurexin interactor calsyntenin-3 promotes excitatory and inhibitory synapse development. Neuron 80: 113-128. doi:10.1016/j.neuron.2013.07.016. doi: 10.1016/j.neuron.2013.07.016
    [69] Uchida Y, Gomi F, Murayama S, et al. (2013) Calsyntenin-3 C-terminal fragment accumulates in dystrophic neurites surrounding aβ plaques in tg2576 mouse and Alzheimer disease brains: its neurotoxic role in mediating dystrophic neurite formation. Am J Pathol 182: 1718-1726. doi:10.1016/j.ajpath.2013.01.014. doi: 10.1016/j.ajpath.2013.01.014
    [70] DeSilva U, D’Arcangelo G, Braden VV, et al. (1997) The human reelin gene: Isolation, sequencing, and mapping on chromosome 7. Genome Res 7: 157-164. doi:10.1101/gr.7.2.157. doi: 10.1101/gr.7.2.157
    [71] Stranahan AM, Erion JR, Wosiski-Kuhn M (2013) Reelin signaling in development, maintenance, and plasticity of neural networks. Ageing Res Rev 12: 815-822. doi:10.1016/j.arr.2013.01.005. doi: 10.1016/j.arr.2013.01.005
    [72] Eastwood SL, Harrison PJ (2003) Interstitial white matter neurons express less reelin and are abnormally distributed in schizophrenia: towards an integration of molecular and morphologic aspects of the neurodevelopmental hypothesis. Mol Psychiatry 8: 821-831. doi:10.1038/sj.mp.4001399. doi: 10.1038/sj.mp.4001371
    [73] Fatemi SH, Stary JM, Egan EA (2002) Reduced blood levels of reelin as a vulnerability factor in pathophysiology of autistic disorder. Cell Mol Neurobiol 22: 139-152. doi:http://dx.doi.org/10.1023/A:1019857620251. doi: 10.1023/A:1019857620251
    [74] Botella-López A, Burgaya F, Gavín R, et al. (2006) Reelin expression and glycosylation patterns are altered in Alzheimer’s disease. Proc Natl Acad Sci U S A 103: 5573-5578. doi:10.1073/pnas.0601279103. doi: 10.1073/pnas.0601279103
    [75] Herring A, Donath A, Steiner KM, et al. (2012) Reelin depletion is an early phenomenon of alzheimer’s pathology. J Alzheimer’s Dis 30: 963-979. doi:10.3233/JAD-2012-112069.
    [76] Chin J, Massaro CM, Palop JJ, et al. (2007) Reelin Depletion in the Entorhinal Cortex of Human Amyloid Precursor Protein Transgenic Mice and Humans with Alzheimer’s Disease. J Neurosci 27.
    [77] Pujadas L, Rossi D, Andrés R, et al. (2014) Reelin delays amyloid-beta fibril formation and rescues cognitive deficits in a model of Alzheimer’s disease. Nat Commun 5: 3443. doi:10.1038/ncomms4443.
    [78] Cuchillo-Ibáñez I, Balmaceda V, Botella-López A, et al. (2013) Beta-Amyloid Impairs Reelin Signaling. PLoS One 8: 1-10. doi:10.1371/journal.pone.0072297.
    [79] Patrick GN, Zukerberg L, Nikolic M, et al. (1999) Conversion of p35 to p25 deregulates Cdk5 activity and promotes neurodegeneration. Nature 402: 615-622. doi:10.1038/45159. doi: 10.1038/45159
    [80] Sakamuro D, Elliott KJ, Wechsler-Reya R, et al. (1996) BIN1 is a novel MYC-interacting protein with features of a tumour suppressor. Nat Genet 14: 69-77. doi:10.1038/ng0996-69. doi: 10.1038/ng0996-69
    [81] Chapuis J, Hansmannel F, Gistelinck M, et al. (2013) Increased expression of BIN1 mediates Alzheimer genetic risk by modulating tau pathology. Mol Psychiatry 18: 1225-1234. doi:10.1038/mp.2013.1. doi: 10.1038/mp.2013.1
    [82] Holler CJ, Davis PR, Beckett TL, et al. (2014) Bridging integrator 1 (BIN1) protein expression increases in the Alzheimer’s disease brain and correlates with neurofibrillary tangle pathology. J Alzheimers Dis 42: 1221-1227. doi:10.3233/JAD-132450.
    [83] Sun L, Tan M-S, Hu N, et al. (2013) Exploring the value of plasma BIN1 as a potential biomarker for alzheimer’s disease. J Alzheimers Dis 37: 291-295. doi:10.3233/JAD-130392.
    [84] Glennon EBC, Whitehouse IJ, Miners JS, et al. (2013) BIN1 Is Decreased in Sporadic but Not Familial Alzheimer’s Disease or in Aging. PLoS One 8. doi:10.1371/journal.pone.0078806.
    [85] Gan-Or Z, Amshalom I, Bar-Shira A, et al. (2015) The Alzheimer disease BIN1 locus as a modifier of GBA-associated Parkinson disease. J Neurol 262: 2443-2447. doi:10.1007/s00415-015-7868-3. doi: 10.1007/s00415-015-7868-3
    [86] Ou SH, Wu F, Harrich D, et al. (1995) Cloning and characterization of a novel cellular protein, TDP-43, that binds to human immunodeficiency virus type 1 TAR DNA sequence motifs. J Virol 69: 3584-3596. http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=189073&tool=pmcentrez&rendertype=abstract.
    [87] Arai T, Mackenzie IRA, Hasegawa M, et al. (2009) Phosphorylated TDP-43 in Alzheimer’s disease and dementia with Lewy bodies. Acta Neuropathol 117: 125-136. doi:10.1007/s00401-008-0480-1. doi: 10.1007/s00401-008-0480-1
    [88] Foulds P, McAuley E, Gibbons L, et al. (2008) TDP-43 protein in plasma may index TDP-43 brain pathology in Alzheimer’s disease and frontotemporal lobar degeneration. Acta Neuropathol 116: 141-146. doi:10.1007/s00401-008-0389-8. doi: 10.1007/s00401-008-0389-8
    [89] Higashi S, Iseki E, Yamamoto R, et al. (2007) Concurrence of TDP-43, tau and alpha-synuclein pathology in brains of Alzheimer’s disease and dementia with Lewy bodies. Brain Res 1184: 284-294. doi:10.1016/j.brainres.2007.09.048. doi: 10.1016/j.brainres.2007.09.048
    [90] Zhang Y-J, Xu Y-F, Cook C, et al. (2009) Aberrant cleavage of TDP-43 enhances aggregation and cellular toxicity. Proc Natl Acad Sci U S A 106: 7607-7612. doi:10.1073/pnas.0900688106. doi: 10.1073/pnas.0900688106
    [91] Tauffenberger A, Chitramuthu BP, Bateman A, et al. (2013) Reduction of polyglutamine toxicity by TDP-43, FUS and progranulin in Huntington’s disease models. Hum Mol Genet 22: 782-794. doi:10.1093/hmg/dds485. doi: 10.1093/hmg/dds485
    [92] Josephs KA, Whitwell JL, Weigand SD, et al. (2014) TDP-43 is a key player in the clinical features associated with Alzheimer’s disease. Acta Neuropathol 127: 811-824. doi:10.1007/s00401-014-1269-z. doi: 10.1007/s00401-014-1269-z
    [93] Spilker C, Braunewell K-H (2003) Calcium-myristoyl switch, subcellular localization, and calcium-dependent translocation of the neuronal calcium sensor protein VILIP-3, and comparison with VILIP-1 in hippocampal neurons. Mol Cell Neurosci 24: 766-778. http://www.ncbi.nlm.nih.gov/pubmed/14664824. Accessed February 15, 2016. doi: 10.1016/S1044-7431(03)00242-2
    [94] Laterza OF, Modur VR, Crimmins DL, et al. (2006) Identification of novel brain biomarkers. Clin Chem 52: 1713-1721. doi:10.1373/clinchem.2006.070912. doi: 10.1373/clinchem.2006.070912
    [95] Braunewell KH (2012) The visinin-like proteins VILIP-1 and VILIP-3 in Alzheimer’s disease-old wine in new bottles. Front Mol Neurosci 5: 20. doi:10.3389/fnmol.2012.00020.
    [96] Chakroborty S, Stutzmann GE (2011) Early calcium dysregulation in Alzheimer’s disease: Setting the stage for synaptic dysfunction. Sci China Life Sci 54: 752-762. doi:10.1007/s11427-011-4205-7. doi: 10.1007/s11427-011-4205-7
    [97] Bezprozvanny I, Mattson MP (2008) Neuronal calcium mishandling and the pathogenesis of Alzheimer’s disease. Trends Neurosci 31: 454-463. doi:10.1016/j.tins.2008.06.005. doi: 10.1016/j.tins.2008.06.005
    [98] Schnurra I, Bernstein HG, Riederer P, et al. (2001) The neuronal calcium sensor protein VILIP-1 is associated with amyloid plaques and extracellular tangles in Alzheimer’s disease and promotes cell death and tau phosphorylation in vitro: a link between calcium sensors and Alzheimer's disease? Neurobiol Dis 8: 900-909. doi:10.1006/nbdi.2001.0432. doi: 10.1006/nbdi.2001.0432
    [99] Lee JM, Blennow K, Andreasen N, et al. (2008) The brain injury biomarker VLP-1 is increased in the cerebrospinal fluid of Alzheimer disease patients. Clin Chem 54: 1617-1623. doi:10.1373/clinchem.2008.104497. doi: 10.1373/clinchem.2008.104497
    [100] Liebl MP, Kaya AM, Tenzer S, et al. (2014) Dimerization of visinin-like protein 1 is regulated by oxidative stress and calcium and is a pathological hallmark of amyotrophic lateral sclerosis. Free Radic Biol Med 72: 41-54. doi:10.1016/j.freeradbiomed.2014.04.008. doi: 10.1016/j.freeradbiomed.2014.04.008
    [101] Stejskal D, Sporova L, Svestak M, et al. (2011) Determination of serum visinin like protein-1 and its potential for the diagnosis of brain injury due to the stroke: a pilot study. Biomed Pap Med Fac Univ Palacký Olomouc Czechoslov 155: 263-268. doi:10.5507/bp.2011.049. doi: 10.5507/bp.2011.049
    [102] Bernstein H-G, Braunewell K-H, Spilker C, et al. (2002) Hippocampal expression of the calcium sensor protein visinin-like protein-1 in schizophrenia. Neuroreport 13: 393-396. http://www.ncbi.nlm.nih.gov/pubmed/11930147. doi: 10.1097/00001756-200203250-00006
    [103] Kester MI, Teunissen CE, Sutphen C, et al. Cerebrospinal fluid VILIP-1 and YKL-40, candidate biomarkers to diagnose, predict and monitor Alzheimer’s disease in a memory clinic cohort. Alzheimers Res Ther 7: 59. doi:10.1186/s13195-015-0142-1.
    [104] Tarawneh R, D’Angelo G, Macy E, et al. (2011) Visinin-like protein-1: diagnostic and prognostic biomarker in Alzheimer disease. Ann Neurol 70: 274-285. doi:10.1002/ana.22448. doi: 10.1002/ana.22448
    [105] Lin Q, Cao Y, Gao J (2014) Serum calreticulin is a negative biomarker in patients with Alzheimer’s disease. Int J Mol Sci 15: 21740-21753. doi:10.3390/ijms151221740. doi: 10.3390/ijms151221740
    [106] Wu J-C, Liang Z-Q, Qin Z-H (2006) Quality control system of the endoplasmic reticulum and related diseases. Acta Biochim Biophys Sin 38: 219-226. doi:10.1111/j.1745-7270.2006.00156.x.
    [107] Bernard-Marissal N, Moumen a., Sunyach C, et al. (2012) Reduced Calreticulin Levels Link Endoplasmic Reticulum Stress and Fas-Triggered Cell Death in Motoneurons Vulnerable to ALS. J Neurosci 32: 4901-4912. doi:10.1523/JNEUROSCI.5431-11. doi: 10.1523/JNEUROSCI.5431-11.2012
    [108] Gelebart P, Opas M, Michalak M (2004) Calreticulin, a Ca2+-binding chaperone of the endoplasmic reticulum. Int J Biochem Cell Biol 37: 260-266. doi:10.1016/j.biocel.2004.02.030.
    [109] Peterson JR, Ora A, Van PN, et al. (1995) Transient, lectin-like association of calreticulin with folding intermediates of cellular and viral glycoproteins. Mol Biol Cell 6: 1173-1184. doi:10.1091/mbc.6.9.1173. doi: 10.1091/mbc.6.9.1173
    [110] Duus K, Hansen PR, Houen G (2008) Interaction of calreticulin with amyloid beta peptide 1–42. Protein Pept Lett 15: 103-107. http://www.ncbi.nlm.nih.gov/pubmed/18221019.. doi: 10.2174/092986608783330459
    [111] Erickson RR, Dunning LM, Olson DA, et al. (2005) In cerebrospinal fluid ER chaperones ERp57 and calreticulin bind beta-amyloid. Biochem Biophys Res Commun 332: 50-57. doi:10.1016/j.bbrc.2005.04.090. doi: 10.1016/j.bbrc.2005.04.090
    [112] Taguchi J, Fujii A, Fujino Y, et al. (2000) Different expression of calreticulin and immunoglobulin binding protein in Alzheimer’s disease brain. Acta Neuropathol 100: 153-160. doi:10.1007/s004019900165. doi: 10.1007/s004019900165
    [113] Luo X, Weber GA, Zheng J, et al. (2003) C1q-calreticulin induced oxidative neurotoxicity: Relevance for the neuropathogenesis of Alzheimer’s disease. J Neuroimmunol 135: 62-71. doi:10.1016/S0165-5728(02)00444-7. doi: 10.1016/S0165-5728(02)00444-7
    [114] Díez-Guerra FJ (2010) Neurogranin, a link between calcium/calmodulin and protein kinase C signaling in synaptic plasticity. IUBMB Life 62: 597-606. doi:10.1002/iub.357. doi: 10.1002/iub.357
    [115] Kester MI, Teunissen CE, Crimmins DL, et al. (2015) Neurogranin as a Cerebrospinal Fluid Biomarker for Synaptic Loss in Symptomatic Alzheimer Disease. JAMA Neurol 72: 1275-1280. doi:10.1001/jamaneurol.2015.1867. doi: 10.1001/jamaneurol.2015.1867
    [116] Fyfe I (2015) Alzheimer disease: neurogranin in the CSF signals early Alzheimer disease and predicts disease progression. Nat Rev Neurol 11: 609. doi:10.1038/nrneurol.2015.178. doi: 10.1038/nrneurol.2015.178
    [117] Portelius E, Zetterberg H, Skillbäck T, et al. (2015) Cerebrospinal fluid neurogranin: relation to cognition and neurodegeneration in Alzheimer’s disease. Brain 138: 3373-3385. doi:10.1093/brain/awv267. doi: 10.1093/brain/awv267
    [118] De Vos A, Jacobs D, Struyfs H, et al. (2015) C-terminal neurogranin is increased in cerebrospinal fluid but unchanged in plasma in Alzheimer’s disease. Alzheimers Dement 11: 1461-1469. doi:10.1016/j.jalz.2015.05.012. doi: 10.1016/j.jalz.2015.05.012
  • Reader Comments
  • © 2016 the Author(s), licensee AIMS Press. This is an open access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0)
通讯作者: 陈斌, bchen63@163.com
  • 1. 

    沈阳化工大学材料科学与工程学院 沈阳 110142

  1. 本站搜索
  2. 百度学术搜索
  3. 万方数据库搜索
  4. CNKI搜索

Metrics

Article views(5952) PDF downloads(1218) Cited by(0)

Article outline

Figures and Tables

Figures(2)

Other Articles By Authors

/

DownLoad:  Full-Size Img  PowerPoint
Return
Return

Catalog