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Theme: Alzheimer's disease: the biomarker revolution - Review

Biomarkers in Alzheimer’s disease: past, present and future

    Katarzyna Gustaw-Rothenberg

    University Hospitals, Case Medical Center and University Memory and Cognition Center, Case Western Reserve University, Cleveland, OH, USA

    Department of Neurodegenerative Diseases, Institute of Agricultural Medicine, 2 Jaczewskiego Str, 20-095, Lublin, Poland

    ,
    Alan Lerner

    University Hospitals, Case Medical Center and University Memory and Cognition Center, Case Western Reserve University, Cleveland, OH, USA

    ,
    David J Bonda

    Department of Pathology, Case Western Reserve University, Cleveland, OH, USA.

    ,
    Hyoung-gon Lee

    Department of Pathology, Case Western Reserve University, Cleveland, OH, USA.

    ,
    Xiongwei Zhu

    Department of Pathology, Case Western Reserve University, Cleveland, OH, USA.

    ,
    George Perry

    Department of Pathology, Case Western Reserve University, Cleveland, OH, USA.

    UTSA Neurosciences Institute and Department of Biology, College of Sciences, University of Texas at San Antonio, San Antonio, TX, USA

    &
    Mark A Smith

    † Author for correspondence

    Department of Pathology, Case Western Reserve University, Cleveland, OH, USA.

    Published Online:https://doi.org/10.2217/bmm.09.86

    Epidemiological and molecular studies suggest that Alzheimer’s disease (AD) has multiple etiologies including genetic mutations, genetic variations affecting susceptibility and environmental factors. These aspects can promote the formation and accumulation of insoluble amyloid-β and hyperphosphorylated tau. Since the disease is multifactorial and clinical diagnosis is highly exclusive, the need for a sensitive, specific and reliable biomarker is crucial. The concept of a biomarker implies sensitivity and specificity relative to the condition being considered. For clinical practice, AD diagnosis has been based on adherence to clinical criteria such as the NINCDS/ADRDA and DSM-IV. A more recent set of diagnostic criteria proposed incorporates imaging findings into the diagnosis of AD. In this article, we consider the most studied candidates or group of candidates for AD biomarkers, including pathological processes and proteins (amyloid-β, tau, oxidative stress, mitochondrial/metabolic changes and cell-cycle processes), or autoantibodies thereto, as well as genetic factors.

    Papers of special note have been highlighted as: ▪ of interest ▪▪ of considerable interest

    Bibliography

    • McKhann G, Drachman D, Folstein M, Katzman R, Price D, Stadlan EM: Clinical diagnosis of Alzheimer’s disease: report of the NINCDS-ADRDA Work Group under the auspices of Department of Health and Human Services Task Force on Alzheimer’s Disease. Neurology34(7),939–944 (1984).▪ Indicates the importance of early diagnosis of Alzheimer’s disease (AD) and presents the first notion of appropriate and realistic clinical applications.
    • Dubois B, Feldman HH, Jacova C et al.: Research criteria for the diagnosis of Alzheimer’s disease: revising the NINCDS-ADRDA criteria. Lancet Neurol.6(8),734–746 (2007).
    • Swets JA: Measuring the accuracy of diagnostic systems. Science240(4857),1285–1293 (1988).
    • Evans DA, Funkenstein HH, Albert MS et al.: Prevalence of Alzheimer’s disease in a community population of older persons. Higher than previously reported. JAMA262(18),2551–2556 (1989).
    • Lerner AJ, Friedland RP, Whitehouse PJ: Uses of biological markers. Alzheimer Dis. Assoc. Disord.6(4),197–200 (1992).
    • Risacher SL, Saykin AJ, West JD, Shen L, Firpi HA, McDonald BC: Baseline MRI predictors of conversion from MCI to probable AD in the ADNI cohort. Curr. Alzheimer Res.6(4),347–361 (2009).
    • Landau SM, Harvey D, Madison CM et al.: Associations between cognitive, functional, and FDG-PET measures of decline in AD and MCI. Neurobiol. Aging (2010) (Epub ahead of print).
    • Leow AD, Yanovsky I, Parikshak N et al.: Alzheimer’s disease neuroimaging initiative: a one-year follow up study using tensor-based morphometry correlating degenerative rates, biomarkers and cognition. Neuroimage45(3),645–655 (2009).
    • Querbes O, Aubry F, Pariente J et al.: Early diagnosis of Alzheimer’s disease using cortical thickness: impact of cognitive reserve. Brain132(Pt 8),2036–2047 (2009).
    • 10  Folstein MF, Folstein SE, McHugh PR: “Mini-mental state”. A practical method for grading the cognitive state of patients for the clinician. J. Psychiatr. Res.12(3),189–198 (1975).
    • 11  Mohs RC, Cohen L: Alzheimer’s Disease Assessment Scale (ADAS). Psychopharmacol. Bull.24(4),627–628 (1988).
    • 12  Ray S, Britschgi M, Herbert C et al.: Classification and prediction of clinical Alzheimer’s diagnosis based on plasma signaling proteins. Nat. Med.13(11),1359–1362 (2007).
    • 13  Hardy J, Selkoe DJ: The amyloid hypothesis of Alzheimer’s disease: progress and problems on the road to therapeutics. Science297(5580),353–356 (2002).
    • 14  Castellani RJ, Nunomura A, Lee HG, Perry G, Smith MA: Phosphorylated tau: toxic, protective, or none of the above. J. Alzheimers Dis.14(4),377–383 (2008).
    • 15  Brouwers N, Sleegers K, Van Broeckhoven C: Molecular genetics of Alzheimer’s disease: an update. Ann. Med.40(8),562–583 (2008).
    • 16  Martinez-Garcia A, Aldudo J, Recuero M et al.: Presenilin 1 polymorphism associated with Alzheimer’s disease in apolipoprotein ε4 carriers. Dement. Geriatr. Cogn. Disord.26(5),440–444 (2008).
    • 17  McShea A, Lee HG, Petersen RB et al.: Neuronal cell cycle re-entry mediates Alzheimer disease-type changes. Biochim. Biophys. Acta1772,467–472 (2007).
    • 18  Moreira PI, Santos MS, Oliveira CR et al.: Alzheimer disease and the role of free radicals in the pathogenesis of the disease. CNS Neurol. Disord. Drug Targets7(1),3–10 (2008).
    • 19  Wang X, Su B, Zheng L, Perry G, Smith MA, Zhu X: The role of abnormal mitochondrial dynamics in the pathogenesis of Alzheimer’s disease. J. Neurochem.109(Suppl. 1),153–159 (2009).
    • 20  Smith MA: Alzheimer disease. Int. Rev. Neurobiol.42,1–54 (1998).
    • 21  Roychaudhuri R, Yang M, Hoshi MM, Teplow DB: Amyloid β-protein assembly and Alzheimer disease. J. Biol. Chem.284(8),4749–4753 (2009).
    • 22  Lee HG, Zhu X, Nunomura A, Perry G, Smith MA: Amyloid β: the alternate hypothesis. Curr. Alzheimer Res.3(1),75–80 (2006).▪▪ Exemplifies our position on the role played by amyloid-β (Aβ) in the pathogensis of AD. That is, Aβ is secondary in the cascade of neurodegeneration that yields AD.
    • 23  Castellani RJ, Lee HG, Zhu X, Nunomura A, Perry G, Smith MA: Neuropathology of Alzheimer disease: pathogenomonic but not pathogenic. Acta Neuropathol. (Berl.)111(6),503–509 (2006).
    • 24  Lee HG, Casadesus G, Zhu X, Joseph JA, Perry G, Smith MA: Perspectives on the amyloid-β cascade hypothesis. J. Alzheimers Dis.6(2),137–145 (2004).
    • 25  Sousa MM, Saraiva MJ: Neurodegeneration in familial amyloid polyneuropathy: from pathology to molecular signaling. Prog. Neurobiol.71(5),385–400 (2003).
    • 26  Selkoe DJ: Alzheimer’s disease results from the cerebral accumulation and cytotoxicity of amyloid β-protein. J. Alzheimers Dis.3(1),75–80 (2001).
    • 27  Greenberg SM, Koo EH, Selkoe DJ, Qiu WQ, Kosik KS: Secreted β-amyloid precursor protein stimulates mitogen-activated protein kinase and enhances tau phosphorylation. Proc. Natl Acad. Sci. USA91(15),7104–7108 (1994).
    • 28  Clark CM, Karlawish JH: Alzheimer disease: current concepts and emerging diagnostic and therapeutic strategies. Ann. Intern. Med.138(5),400–410 (2003).
    • 29  Craft JM, Watterson DM, Hirsch E, Van Eldik LJ: Interleukin 1 receptor antagonist knockout mice show enhanced microglial activation and neuronal damage induced by intracerebroventricular infusion of human β-amyloid. J. Neuroinflammation2,15 (2005).
    • 30  Weksler ME, Relkin N, Turkenich R, LaRusse S, Zhou L, Szabo P: Patients with Alzheimer disease have lower levels of serum anti-amyloid peptide antibodies than healthy elderly individuals. Exp. Gerontol.37(7),943–948 (2002).▪▪ Presents the challenges previously associated with utilizing serum levels of Aβ for disease diagnosis.
    • 31  Du Y, Dodel R, Hampel H et al.: Reduced levels of amyloid β-peptide antibody in Alzheimer disease. Neurology57(5),801–805 (2001).
    • 32  Mruthinti S, Buccafusco JJ, Hill WD et al.: Autoimmunity in Alzheimer’s disease: increased levels of circulating IgGs binding Aβ and RAGE peptides. Neurobiol. Aging25(8),1023–1032 (2004).
    • 33  Biere AL, Ostaszewski B, Stimson ER, Hyman BT, Maggio JE, Selkoe DJ: Amyloid β-peptide is transported on lipoproteins and albumin in human plasma. J. Biol. Chem.271(51),32916–32922 (1996).
    • 34  Sagare A, Deane R, Bell RD et al.: Clearance of amyloid-β by circulating lipoprotein receptors. Nat. Med.13(9),1029–1031 (2007).
    • 35  Fullwood NJ, Hayashi Y, Allsop D: Plasma amyloid-β concentrations in Alzheimer’s disease: an alternative hypothesis. Lancet Neurol.5(12),1000–1001; author reply 1002–1003 (2006).
    • 36  Oh ES, Troncoso JC, Fangmark Tucker SM: Maximizing the potential of plasma amyloid-β as a diagnostic biomarker for Alzheimer’s disease. Neuromolecular Med.10(3),195–207 (2008).
    • 37  Blennow K: Cerebrospinal fluid protein biomarkers for Alzheimer’s disease. NeuroRx1(2),213–225 (2004).
    • 38  Schenk D, Barbour R, Dunn W et al.: Immunization with amyloid-β attenuates Alzheimer-disease-like pathology in the PDAPP mouse. Nature400(6740),173–177 (1999).
    • 39  Wilcock DM, Gordon MN, Ugen KE et al.: Number of Aβ inoculations in APP+PS1 transgenic mice influences antibody titers, microglial activation, and congophilic plaque levels. DNA Cell Biol.20(11),731–736 (2001).
    • 40  Gustaw KA, Garrett MR, Lee HG et al.: Antigen–antibody dissociation in Alzheimer disease: a novel approach to diagnosis. J. Neurochem.106(3),1350–1356 (2008).▪▪ Introduces our novel method of antibody–antigen dissociation for serum diagnosis of AD.
    • 41  Li Q, Cao C, Chackerian B et al.: Overcoming antigen masking of anti-amyloid-β antibodies reveals breaking of B cell tolerance by virus-like particles in amyloid-β immunized amyloid precursor protein transgenic mice. BMC Neurosci.5,21 (2004).
    • 42  Gustaw-Rothenberg KA, Siedlak SL, Bonda DJ et al.: Dissociated amyloid-β antibody levels during the progression of Alzheimer’s disease: a population-based study. Exp. Gerontol.45,47–52 (2010).
    • 43  Ida N, Hartmann T, Pantel J et al.: Analysis of heterogeneous A4 peptides in human cerebrospinal fluid and blood by a newly developed sensitive western blot assay. J. Biol. Chem.271(37),22908–22914 (1996).
    • 44  Quesada JJ, Ferrucci L, Calvani D, Valente C, Salani B, Bavazzano A: Formal education as an effect modifier of the relationship between Mini-Mental State Examination score and IADLs disability in the older population. Aging (Milano)9(3),175–179 (1997).
    • 45  Iqbal K, Zaidi T, Thompson CH, Merz PA, Wisniewski HM: Alzheimer paired helical filaments: bulk isolation, solubility, and protein composition. Acta Neuropathol. (Berl.)62(3),167–177 (1984).
    • 46  Grundke-Iqbal I, Iqbal K, Tung YC, Quinlan M, Wisniewski HM, Binder LI: Abnormal phosphorylation of the microtubule-associated protein tau in Alzheimer cytoskeletal pathology. Proc. Natl Acad. Sci. USA83(13),4913–4917 (1986).
    • 47  Lee HG, Perry G, Moreira PI et al.: Tau phosphorylation in Alzheimer’s disease: pathogen or protector? Trends Mol. Med.11(4),164–169 (2005).
    • 48  Alonso AC, Grundke-Iqbal I, Iqbal K: Alzheimer’s disease hyperphosphorylated tau sequesters normal tau into tangles of filaments and disassembles microtubules. Nat. Med.2(7),783–787 (1996).
    • 49  Cash AD, Aliev G, Siedlak SL et al.: Microtubule reduction in Alzheimer’s disease and aging is independent of tau filament formation. Am. J. Pathol.162(5),1623–1627 (2003).
    • 50  Brion JP, Passarier H, Nunez J, Flament-Durand J: Immunologic determinants of tau protein are present in neurofibrillary tangles of Alzheimer’s disease. Arch. Biol.95,229–235 (1985).
    • 51  Kanemaru K, Takio K, Miura R, Titani K, Ihara Y: Fetal-type phosphorylation of the tau in paired helical filaments. J. Neurochem.58(5),1667–1675 (1992).
    • 52  Goedert M, Jakes R, Crowther RA et al.: The abnormal phosphorylation of tau protein at Ser-202 in Alzheimer disease recapitulates phosphorylation during development. Proc. Natl Acad. Sci. USA90(11),5066–5070 (1993).
    • 53  Pope WB, Lambert MP, Leypold B et al.: Microtubule-associated protein tau is hyperphosphorylated during mitosis in the human neuroblastoma cell line SH-SY5Y. Exp. Neurol.126(2),185–194 (1994).
    • 54  Arendt T, Holzer M, Grossmann A, Zedlick D, Bruckner MK: Increased expression and subcellular translocation of the mitogen activated protein kinase kinase and mitogen-activated protein kinase in Alzheimer’s disease. Neuroscience68(1),5–18 (1995).
    • 55  Vincent I, Rosado M, Davies P: Mitotic mechanisms in Alzheimer’s disease? J. Cell Biol.132(3),413–425 (1996).
    • 56  Ledesma MD, Correas I, Avila J, Diaz-Nido J: Implication of brain Cdc2 and MAP2 kinases in the phosphorylation of tau protein in Alzheimer’s disease. FEBS Lett.308(2),218–224 (1992).
    • 57  Baumann K, Mandelkow EM, Biernat J, Piwnica-Worms H, Mandelkow E: Abnormal Alzheimer-like phosphorylation of tau-protein by cyclin-dependent kinases cdk2 and cdk5. FEBS Lett.336(3),417–424 (1993).
    • 58  McShea A, Wahl AF, Smith MA: Re-entry into the cell cycle: a mechanism for neurodegeneration in Alzheimer disease. Med. Hypotheses52(6),525–527 (1999).
    • 59  Zhu X, Rottkamp CA, Raina AK et al.: Neuronal CDK7 in hippocampus is related to aging and Alzheimer disease. Neurobiol. Aging21(6),807–813 (2000).
    • 60  Raina AK, Zhu X, Rottkamp CA, Monteiro M, Takeda A, Smith MA: Cyclin’ toward dementia: cell cycle abnormalities and abortive oncogenesis in Alzheimer disease. J. Neurosci. Res.61(2),128–133 (2000).
    • 61  Hampel H, Broich K, Hoessler Y, Pantel J: Biological markers for early detection and pharmacological treatment of Alzheimer’s disease. Dialogues Clin. Neurosci.11(2),141–157 (2009).▪ Provides a thorough overview on the current possibility for early detection and diagnosis of AD. Discusses the difficulty of such a diagnosis and demonstrates the value of our findings.
    • 62  Heckmann JM, Low WC, de Villiers C et al.: Novel presenilin 1 mutation with profound neurofibrillary pathology in an indigenous Southern African family with early-onset Alzheimer’s disease. Brain127(Pt 1),133–142 (2004).
    • 63  Wong PC, Zheng H, Chen H et al.: Presenilin 1 is required for Notch1 and DII1 expression in the paraxial mesoderm. Nature387(6630),288–292 (1997).
    • 64  Struhl G, Greenwald I: Presenilin is required for activity and nuclear access of Notch in Drosophila. Nature398(6727),522–525 (1999).
    • 65  Ye Y, Lukinova N, Fortini ME: Neurogenic phenotypes and altered Notch processing in Drosophila presenilin mutants. Nature398(6727),525–529 (1999).
    • 66  Wodarz A, Nusse R: Mechanisms of Wnt signaling in development. Annu. Rev. Cell Dev. Biol.14,59–88 (1998).
    • 67  Polakis P: The oncogenic activation of β-catenin. Curr. Opin. Genet. Dev.9(1),15–21 (1999).
    • 68  Janicki SM, Monteiro MJ: Presenilin overexpression arrests cells in the G1 phase of the cell cycle. Arrest potentiated by the Alzheimer’s disease PS2(N141I)mutant. Am. J. Pathol.155(1),135–144 (1999).
    • 69  Mattson MP, Guo Q, Furukawa K, Pedersen WA: Presenilins, the endoplasmic reticulum, and neuronal apoptosis in Alzheimer’s disease. J. Neurochem.70(1),1–14 (1998).
    • 70  Lindwall G, Cole RD: Phosphorylation affects the ability of tau protein to promote microtubule assembly. J. Biol. Chem.259(8),5301–5305 (1984).
    • 71  Wolozin B, Iwasaki K, Vito P et al.: Participation of presenilin 2 in apoptosis: enhanced basal activity conferred by an Alzheimer mutation. Science274(5293),1710–1713 (1996).
    • 72  Park DS, Morris EJ, Padmanabhan J, Shelanski ML, Geller HM, Greene LA: Cyclin-dependent kinases participate in death of neurons evoked by DNA-damaging agents. J. Cell Biol.143(2),457–467 (1998).
    • 73  Giovanni A, Wirtz-Brugger F, Keramaris E, Slack R, Park DS: Involvement of cell cycle elements, cyclin-dependent kinases, pRb, and E2F x DP, in β-amyloid-induced neuronal death. J. Biol. Chem.274(27),19011–19016 (1999).
    • 74  Carter DB: The interaction of amyloid-β with ApoE. Subcell. Biochem.38,255–272 (2005).
    • 75  Farrer LA, Cupples LA, Haines JL et al.: Effects of age, sex, and ethnicity on the association between apolipoprotein E genotype and Alzheimer disease. A meta-analysis. APOE and Alzheimer Disease Meta Analysis Consortium. JAMA278(16),1349–1356 (1997).
    • 76  Van Duijn CM, Clayton DG, Chandra V et al.: Interaction between genetic and environmental risk factors for Alzheimer’s disease: a reanalysis of case–control studies. EURODEM Risk Factors Research Group. Genet. Epidemiol.11(6),539–551 (1994).
    • 77  Potkin SG, Guffanti G, Lakatos A et al.: Hippocampal atrophy as a quantitative trait in a genome-wide association study identifying novel susceptibility genes for Alzheimer’s disease. PLoS ONE4(8),e6501 (2009).
    • 78  Markesbery WR: Oxidative stress hypothesis in Alzheimer’s disease. Free Radic. Biol. Med.23(1),134–147 (1997).
    • 79  Barni S, Sciola L, Spano A, Pippia P: Static cytofluorometry and fluorescence morphology of mitochondria and DNA in proliferating fibroblasts. Biotech. Histochem.71(2),66–70 (1996).
    • 80  Hirai K, Aliev G, Nunomura A et al.: Mitochondrial abnormalities in Alzheimer’s disease. J. Neurosci.21(9),3017–3023 (2001).
    • 81  Sousa M, Barros A, Silva J, Tesarik J: Developmental changes in calcium content of ultrastructurally distinct subcellular compartments of preimplantation human embryos. Mol. Hum. Reprod.3(2),83–90 (1997).
    • 82  Zhu X, Lee HG, Perry G, Smith MA: Alzheimer disease, the two-hit hypothesis: an update. Biochim. Biophys. Acta1772(4),494–502 (2007).
    • 83  Ferrer I, Blanco R, Carmona M, Puig B: Phosphorylated mitogen-activated protein kinase (MAPK/ERK-P), protein kinase of 38 kDa (p38-P), stress-activated protein kinase (SAPK/JNK-P), and calcium/calmodulin-dependent kinase II (CaM kinase II) are differentially expressed in tau deposits in neurons and glial cells in tauopathies. J. Neural Transm.108(12),1397–1415 (2001).
    • 84  Zhu X, Lee HG, Raina AK, Perry G, Smith MA: The role of mitogen-activated protein kinase pathways in Alzheimer’s disease. Neurosignals11(5),270–281 (2002).
    • 85  Zhang L, Jope RS: Oxidative stress differentially modulates phosphorylation of ERK, p38 and CREB induced by NGF or EGF in PC12 cells. Neurobiol. Aging20(3),271–278 (1999).
    • 86  Smith MA, Sayre LM, Monnier VM, Perry G: Radical AGEing in Alzheimer’s disease. Trends Neurosci.18(4),172–176 (1995).
    • 87  Luo Y, Bond JD, Ingram VM: Compromised mitochondrial function leads to increased cytosolic calcium and to activation of MAP kinases. Proc. Natl Acad. Sci. USA94(18),9705–9710 (1997).
    • 88  Takeda A, Perry G, Abraham NG et al.: Overexpression of heme oxygenase in neuronal cells, the possible interaction with tau. J. Biol. Chem.275(8),5395–5399 (2000).
    • 89  Zhu X, Raina AK, Perry G, Smith MA: Alzheimer’s disease: the two-hit hypothesis. Lancet Neurol.3(4),219–226 (2004).
    • 90  Zhu X, Castellani RJ, Takeda A et al.: Differential activation of neuronal ERK, JNK/SAPK and p38 in Alzheimer disease: the ‘two hit’ hypothesis. Mech. Ageing Dev.123(1),39–46 (2001).
    • 91  Nagy ZS, Smith MZ, Esiri MM, Barnetson L, Smith AD: Hyperhomocysteinaemia in Alzheimer’s disease and expression of cell cycle markers in the brain. J. Neurol. Neurosurg. Psychiatry69(4),565–566 (2000).
    • 92  Elledge SJ: Cell cycle checkpoints: preventing an identity crisis. Science274(5293),1664–1672 (1996).
    • 93  Padmanabhan J, Park DS, Greene LA, Shelanski ML: Role of cell cycle regulatory proteins in cerebellar granule neuron apoptosis. J. Neurosci.19(20),8747–8756 (1999).
    • 94  Gartner U, Holzer M, Arendt T: Elevated expression of p21ras is an early event in Alzheimer’s disease and precedes neurofibrillary degeneration. Neuroscience91(1),1–5 (1999).
    • 95  Lee HG, Casadesus G, Nunomura A et al.: The neuronal expression of MYC causes a neurodegenerative phenotype in a novel transgenic mouse. Am. J. Pathol.174(3),891–897 (2009).
    • 96  McShea A, Lee HG, Petersen RB et al.: Neuronal cell cycle re-entry mediates Alzheimer disease-type changes. Biochim. Biophys. Acta1772(4),467–472 (2007).
    • 97  Ledoux S, Rebai N, Dagenais A et al.: Amyloid precursor protein in peripheral mononuclear cells is up-regulated with cell activation. J. Immunol.150(12),5566–5575 (1993).
    • 98  Suzuki T, Oishi M, Marshak DR, Czernik AJ, Nairn AC, Greengard P: Cell cycle-dependent regulation of the phosphorylation and metabolism of the Alzheimer amyloid precursor protein. EMBO J.13(5),1114–1122 (1994).
    • 99  Whitson JS, Selkoe DJ, Cotman CW: Amyloid-β protein enhances the survival of hippocampal neurons in vitro. Science243(4897),1488–1490 (1989).
    • 100  McDonald DR, Bamberger ME, Combs CK, Landreth GE: β-amyloid fibrils activate parallel mitogen-activated protein kinase pathways in microglia and THP1 monocytes. J. Neurosci.18(12),4451–4460 (1998).
    • 101  Rapoport M, Ferreira A: PD98059 prevents neurite degeneration induced by fibrillar β-amyloid in mature hippocampal neurons. J. Neurochem.74(1),125–133 (2000).
    • 102  Busser J, Geldmacher DS, Herrup K: Ectopic cell cycle proteins predict the sites of neuronal cell death in Alzheimer’s disease brain. J. Neurosci.18,2801–2807 (1998).
    • 103  Koliatsos VE: Biological therapies for Alzheimer’s disease: focus on trophic factors. Crit. Rev. Neurobiol.10(2),205–238 (1996).
    • 104  Stopa EG, Gonzalez AM, Chorsky R et al.: Basic fibroblast growth factor in Alzheimer’s disease. Biochem. Biophys. Res. Commun.171(2),690–696 (1990).
    • 105  Crutcher KA, Scott SA, Liang S, Everson WV, Weingartner J: Detection of NGF-like activity in human brain tissue: increased levels in Alzheimer’s disease. J. Neurosci.13(6),2540–2550 (1993).
    • 106  van der Wal EA, Gomez-Pinilla F, Cotman CW: Transforming growth factor-β1 is in plaques in Alzheimer and Down pathologies. Neuroreport4(1),69–72 (1993).
    • 107  Lesort M, Johnson GV: Insulin-like growth factor-1 and insulin mediate transient site-selective increases in tau phosphorylation in primary cortical neurons. Neuroscience99(2),305–316 (2000).
    • 108  Russell JW, Windebank AJ, Schenone A, Feldman EL: Insulin-like growth factor-I prevents apoptosis in neurons after nerve growth factor withdrawal. J. Neurobiol.36(4),455–467 (1998).
    • 109  Raina AK, Hochman A, Zhu X et al.: Abortive apoptosis in Alzheimer’s disease. Acta Neuropathol. (Berl).101(4),305–310 (2001).
    • 110  Yang Y, Mufson EJ, Herrup K: Neuronal cell death is preceded by cell cycle events at all stages of Alzheimer’s disease. J. Neurosci.23(7),2557–2563 (2003).
    • 111  Spremo-Potparevic B, Zivkovic L, Djelic N, Plecas-Solarovic B, Smith MA, Bajic V: Premature centromere division of the X chromosome in neurons in Alzheimer’s disease. J. Neurochem.106(5),2218–2223 (2008).
    • 112  Bowser R, Smith MA: Cell cycle proteins in Alzheimer’s disease: plenty of wheels but no cycle. J. Alzheimers Dis.4(3),249–254 (2002).