Skip to main content
NCBI home page
Neuroscience Bulletin logoLink to Neuroscience Bulletin
. 2012 Nov 21;29(1):111–120. doi: 10.1007/s12264-012-1287-6

Combination of Aβ clearance and neurotrophic factors as a potential treatment for Alzheimer’s disease

Lian-Feng Lin 1, Min-Jing Liao 1,4, Xiao-Yan Xue 5, Wei Zhang 1, Li Yan 1, Liang Cai 1, Xiao-Wen Zhou 1, Xing Zhou 1, Huan-Min Luo 1,2,3,✉
PMCID: PMC5561854  PMID: 23179066

Abstract

There is no effective drug to treat Alzheimer’s disease (AD), a neurodegenerative disease affecting an estimated 30 million people around the world. Strongly supported by preclinical and clinical studies, amyloid-beta (Aβ) may be a target for developing drugs against AD. Meanwhile, the fact that localized neuronal death/loss and synaptic impairment occur in AD should also be considered. Neuronal regeneration, which does not occur normally in the mammalian central nervous system, can be promoted by neurotrophic factors (NTFs). Evidence from clinical trials has shown that both Aβ clearance and NTFs are potentially effective in treating AD, thus a new approach combining Aβ clearance and administration of NTFs may be an effective therapeutic strategy.

Keywords: Alzheimer’s disease, amyloid-beta, neurotrophic factors, treatment

Footnotes

These authors contributed equally to this review.

References

  • [1].Lin L.F., Luo H.M. Screening of treatment targets for Alzheimer’s disease from the molecular mechanisms of impairment by β-amyloid aggregation and tau hyperphosphorylation. Neurosci Bull. 2011;27:53–60. doi: 10.1007/s12264-011-1040-6. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [2].Holtzman D.M., Morris J.C., Goate A.M. Alzheimer’s disease: the challenge of the second century. Sci Transl Med. 2011;3:77sr71. doi: 10.1126/scitranslmed.3002369. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [3].Winslow B.T., Onysko M.K., Stob C.M., Hazlewood K.A. Treatment of Alzheimer disease. Am Fam Physician. 2011;83:1403–1412. [PubMed] [Google Scholar]
  • [4].Aisen P.S., Cummings J., Schneider L.S. Symptomatic and nonamyloid/tau based pharmacologic treatment for Alzheimer disease. Cold Spring Harb Perspect Med. 2012;2:a006395. doi: 10.1101/cshperspect.a006395. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [5].Olivares D., Deshpande V.K., Shi Y., Lahiri D.K., Greig N.H., Rogers J.T., et al. N-Methyl D-Aspartate (NMDA) receptor antagonists and memantine treatment for Alzheimer’s disease, vascular dementia and Parkinson’s disease. Curr Alzheimer Res. 2012;9(6):746–758. doi: 10.2174/156720512801322564. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [6].Jo J., Whitcomb D.J., Olsen K.M., Kerrigan T.L., Lo S.C., Bru-Mercier G., et al. Abeta(1–42) inhibition of LTP is mediated by a signaling pathway involving caspase-3, Akt1 and GSK-3beta. Nat Neurosci. 2011;14(5):545–547. doi: 10.1038/nn.2785. [DOI] [PubMed] [Google Scholar]
  • [7].Shankar G.M., Li S., Mehta T.H., Garcia-Munoz A., Shepardson N.E., Smith I., et al. Amyloid-beta protein dimers isolated directly from Alzheimer’s brains impair synaptic plasticity and memory. Nat Med. 2008;14:837–842. doi: 10.1038/nm1782. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [8].Shipton OA, Leitz JR, Dworzak J, Acton CE, Tunbridge EM, Denk F, et al. Tau protein is required for amyloid ta-induced impairment of hippocampal long-term potentiation. J Neurosci. 2011;31:1688–1692. doi: 10.1523/JNEUROSCI.2610-10.2011. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [9].Peng S., Garzon D.J., Marchese M., Klein W., Ginsberg S.D., Francis B.M., et al. Decreased brain-derived neurotrophic factor depends on amyloid aggregation state in transgenic mouse models of Alzheimer’s disease. J Neurosci. 2009;29:9321–9329. doi: 10.1523/JNEUROSCI.4736-08.2009. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [10].Van Muiswinkel F.L., Veerhuis R., Eikelenboom P. Amyloid beta protein primes cultured rat microglial cells for an enhanced phorbol 12-myristate 13-acetate-induced respiratory burst activity. J Neurochem. 1996;66:2468–2476. doi: 10.1046/j.1471-4159.1996.66062468.x. [DOI] [PubMed] [Google Scholar]
  • [11].Hensley K., Carney J.M., Mattson M.P., Aksenova M., Harris M., Wu J.F., et al. A model for beta-amyloid aggregation and neurotoxicity based on free radical generation by the peptide: relevance to Alzheimer disease. Proc Natl Acad Sci U S A. 1994;91:3270–3274. doi: 10.1073/pnas.91.8.3270. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [12].Gotz J., Chen F., van Dorpe J., Nitsch R.M. Formation of neurofibrillary tangles in P301l tau transgenic mice induced by Abeta 42 fibrils. Science. 2001;293:1491–1495. doi: 10.1126/science.1062097. [DOI] [PubMed] [Google Scholar]
  • [13].Bell R.D., Zlokovic B.V. Neurovascular mechanisms and blood-brain barrier disorder in Alzheimer’s disease. Acta Neuropathol. 2009;118:103–113. doi: 10.1007/s00401-009-0522-3. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [14].Serlin Y., Levy J., Shalev H. Vascular pathology and bloodbrain barrier disruption in cognitive and psychiatric complications of type 2 diabetes mellitus. Cardiovasc Psychiatry Neurol. 2011;2011:609202. doi: 10.1155/2011/609202. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [15].Yokel R.A. Blood-brain barrier flux of aluminum, manganese, iron and other metals suspected to contribute to metalinduced neurodegeneration. J Alzheimer’s Dis. 2006;10:223–253. doi: 10.3233/jad-2006-102-309. [DOI] [PubMed] [Google Scholar]
  • [16].Plassman B.L., Havlik R.J., Steffens D.C., Helms M.J., Newman T.N., Drosdick D., et al. Documented head injury in early adulthood and risk of Alzheimer’s disease and other dementias. Neurology. 2000;55:1158–1166. doi: 10.1212/WNL.55.8.1158. [DOI] [PubMed] [Google Scholar]
  • [17].Lye T.C., Shores E.A. Traumatic brain injury as a risk factor for Alzheimer’s disease: a review. Neuropsychol Rev. 2000;10:115–129. doi: 10.1023/A:1009068804787. [DOI] [PubMed] [Google Scholar]
  • [18].Sotiropoulos I., Catania C., Pinto L.G., Silva R., Pollerberg G.E., Takashima A., et al. Stress acts cumulatively to precipitate Alzheimer’s disease-like tau pathology and cognitive deficits. J Neurosci. 2011;31:7840–7847. doi: 10.1523/JNEUROSCI.0730-11.2011. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [19].Tran T.T., Srivareerat M., Alkadhi K.A. Chronic psychosocial stress accelerates impairment of long-term memory and late-phase long-term potentiation in an at-risk model of Alzheimer’s disease. Hippocampus. 2011;21:724–732. doi: 10.1002/hipo.20790. [DOI] [PubMed] [Google Scholar]
  • [20].Keller J.N. Interplay between oxidative damage, protein synthesis, and protein degradation in Alzheimer’s disease. J Biomed Biotechnol. 2006;2006:1–3. doi: 10.1155/JBB/2006/12129. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [21].Ding Q.X., Dimayuga E., Keller J.N. Oxidative damage, protein synthesis, and protein degradation in Alzheimer’s disease. Current Alzheimer Res. 2007;4:73–79. doi: 10.2174/156720507779939788. [DOI] [PubMed] [Google Scholar]
  • [22].Laxton A.W., Tang-Wai D.F., McAndrews M.P., Zumsteg D., Wennberg R., Keren R., et al. A Phase I trial of deep brain stimulation of memory circuits in Alzheimer’s disease. Ann Neurol. 2010;68:521–534. doi: 10.1002/ana.22089. [DOI] [PubMed] [Google Scholar]
  • [23].Bentwich J., Dobronevsky E., Aichenbaum S., Shorer R., Peretz R., Khaigrekht M., et al. Beneficial effect of repetitive transcranial magnetic stimulation combined with cognitive training for the treatment of Alzheimer’s disease: a proof of concept study. J Neural Transmission. 2011;118:463–471. doi: 10.1007/s00702-010-0578-1. [DOI] [PubMed] [Google Scholar]
  • [24].Levy Y.S., Gilgun-Sherki Y., Melamed E., Offen D. Therapeutic potential of neurotrophic factors in neurodegenerative diseases. BioDrugs. 2005;19:97–127. doi: 10.2165/00063030-200519020-00003. [DOI] [PubMed] [Google Scholar]
  • [25].Ji C., Song C., Zuo P. The mechanism of memory impairment induced by Abeta chronic administration involves imbalance between cytokines and neurotrophins in the rat hippocampus. Curr Alzheimer Res. 2011;8:410–420. doi: 10.2174/156720511795745366. [DOI] [PubMed] [Google Scholar]
  • [26].Caraci F., Copani A., Nicoletti F., Drago F. Depression and Alzheimer’s disease: neurobiological links and common pharmacological targets. Eur J Pharmacol. 2010;626:64–71. doi: 10.1016/j.ejphar.2009.10.022. [DOI] [PubMed] [Google Scholar]
  • [27].Ciobica A., Padurariu M., Bild W., Stefanescu C. Cardiovascular risk factors as potential markers for mild cognitive impairment and Alzheimer’s disease. Psychiatr Danub. 2011;23:340–346. [PubMed] [Google Scholar]
  • [28].Trudeau F., Gagnon S., Massicotte G. Hippocampal synaptic plasticity and glutamate receptor regulation: influences of diabetes mellitus. Eur J Pharmacol. 2004;490:177–186. doi: 10.1016/j.ejphar.2004.02.055. [DOI] [PubMed] [Google Scholar]
  • [29].Miners J.S., Van Helmond Z., Chalmers K., Wilcock G., Love S., Kehoe P.G. Decreased expression and activity of neprilysin in Alzheimer disease are associated with cerebral amyloid angiopathy. J Neuropathol Exp Neurol. 2006;65:1012–1021. doi: 10.1097/01.jnen.0000240463.87886.9a. [DOI] [PubMed] [Google Scholar]
  • [30].El-Amouri S.S., Zhu H., Yu J., Marr R., Verma I.M., Kindy M.S. Neprilysin: An enzyme candidate to slow the progression of Alzheimer’s disease. American J Pathology. 2008;172:1342–1354. doi: 10.2353/ajpath.2008.070620. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [31].Miners J.S., Kehoe P., Love S. Neprilysin protects against cerebral amyloid angiopathy and Abeta-induced degeneration of cerebrovascular smooth muscle cells. Brain Pathol. 2011;21(5):594–605. doi: 10.1111/j.1750-3639.2011.00486.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [32].Nicholls D.G. Mitochondrial calcium function and dysfunction in the central nervous system. Biochim Biophys Acta. 2009;1787:1416–1424. doi: 10.1016/j.bbabio.2009.03.010. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [33].Duchen M.R. Mitochondria in health and disease: perspectives on a new mitochondrial biology. Mol Aspects Med. 2004;25:365–451. doi: 10.1016/j.mam.2004.03.001. [DOI] [PubMed] [Google Scholar]
  • [34].Kim K., Lee S.G., Kegelman T.P., Su Z.Z., Das S.K., Dash R., et al. Role of excitatory amino acid transporter-2 (EAAT2) and glutamate in neurodegeneration: opportunities for developing novel therapeutics. J Cell Physiol. 2011;226:2484–2493. doi: 10.1002/jcp.22609. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [35].Scott H.A., Gebhardt F.M., Mitrovic A.D., Vandenberg R.J., Dodd P.R. Glutamate transporter variants reduce glutamate uptake in Alzheimer’s disease. Neurobiol Aging. 2011;32:553 e551–553 e511. doi: 10.1016/j.neurobiolaging.2010.03.008. [DOI] [PubMed] [Google Scholar]
  • [36].Guillozet-Bongaarts A.L., Garcia-Sierra F., Reynolds M.R., Horowitz P.M., Fu Y.F., Wang T.Y., et al. Tau truncation during neurofibrillary tangle evolution in Alzheimer’s disease. Neurobiol Aging. 2005;26:1015–1022. doi: 10.1016/j.neurobiolaging.2004.09.019. [DOI] [PubMed] [Google Scholar]
  • [37].Pei J.J., Braak H., Gong C.X., Grundke-Iqbal I., Iqbal K., Winblad B., et al. Up-regulation of cell division cycle (cdc) 2 kinase in neurons with early stage Alzheimer’s disease neurofibrillary degeneration. Acta Neuropathol. 2002;104:369–376. doi: 10.1007/s00401-002-0565-1. [DOI] [PubMed] [Google Scholar]
  • [38].Lee D.C., Rizer J., Selenica M.L., Reid P., Kraft C., Johnson A., et al. LPS-induced inflammation exacerbates phospho-tau pathology in rTg4510 mice. J Neuroinflammation. 2010;7:56. doi: 10.1186/1742-2094-7-56. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [39].Nagele R.G., Wegiel J., Venkataraman V., Imaki H., Wang K.C., Wegiel J. Contribution of glial cells to the development of amyloid plaques in Alzheimer’s disease. Neurobiol Aging. 2004;25:663–674. doi: 10.1016/j.neurobiolaging.2004.01.007. [DOI] [PubMed] [Google Scholar]
  • [40].Griffin R., Nally R., Nolan Y., McCartney Y., Linden J., Lynch M.A. The age-related attenuation in long-term potentiation is associated with microglial activation. J Neurochem. 2006;99:1263–1272. doi: 10.1111/j.1471-4159.2006.04165.x. [DOI] [PubMed] [Google Scholar]
  • [41].Farfara D., Lifshitz V., Frenkel D. Neuroprotective and neurotoxic properties of glial cells in the pathogenesis of Alzheimer’s disease. J Cell Mol Med. 2008;12:762–780. doi: 10.1111/j.1582-4934.2008.00314.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [42].Ha C., Ryu J., Park C.B. Metal ions differentially influence the aggregation and deposition of Alzheimer’s beta-amyloid on a solid template. Biochemistry. 2007;46:6118–6125. doi: 10.1021/bi7000032. [DOI] [PubMed] [Google Scholar]
  • [43].Zatta P., Drago D., Bolognin S., Sensi S.L. Alzheimer’s disease, metal ions and metal homeostatic therapy. Trends Pharmacol Sci. 2009;30:346–355. doi: 10.1016/j.tips.2009.05.002. [DOI] [PubMed] [Google Scholar]
  • [44].Oakley H., Cole S.L., Logan S., Maus E., Shao P., Craft J., et al. Intraneuronal beta-amyloid aggregates, neurodegeneration, and neuron loss in transgenic mice with five familial Alzheimer’s disease mutations: Potential factors in amyloid plaque formation. J Neurosci. 2006;26:10129–10140. doi: 10.1523/JNEUROSCI.1202-06.2006. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [45].Janssen J.C., Beck J.A., Campbell T.A., Dickinson A., Fox N.C., Harvey R.J., et al. Early onset familial Alzheimer’s disease: Mutation frequency in 31 families. Neurology. 2003;60:235–239. doi: 10.1212/01.WNL.0000042088.22694.E3. [DOI] [PubMed] [Google Scholar]
  • [46].Leoni V. The effect of apolipoprotein E (ApoE) genotype on biomarkers of amyloidogenesis, tau pathology and neurodegeneration in Alzheimer’s disease. Clin Chem Lab Med. 2011;49:375–383. doi: 10.1515/cclm.2011.088. [DOI] [PubMed] [Google Scholar]
  • [47].Hardy J., Orr H. The genetics of neurodegenerative diseases. J Neurochem. 2006;97:1690–1699. doi: 10.1111/j.1471-4159.2006.03979.x. [DOI] [PubMed] [Google Scholar]
  • [48].Rovelet-Lecrux A., Hannequin D., Raux G., Le Meur N., Laquerriere A., Vital A., et al. APP locus duplication causes autosomal dominant early-onset Alzheimer disease with cerebral amyloid angiopathy. Nat Genet. 2006;38:24–26. doi: 10.1038/ng1718. [DOI] [PubMed] [Google Scholar]
  • [49].Barthel H., Luthardt J., Becker G., Patt M., Hammerstein E., Hartwig K., et al. Individualized quantification of brain betaamyloid burden: results of a proof of mechanism phase 0 florbetaben PET trial in patients with Alzheimer’s disease and healthy controls. Eur J Nucl Med Mol Imaging. 2011;38:1702–1714. doi: 10.1007/s00259-011-1821-1. [DOI] [PubMed] [Google Scholar]
  • [50].Barthel H., Gertz H.J., Dresel S., Peters O., Bartenstein P., Buerger K., et al. Cerebral amyloid-beta PET with florbetaben (18F) in patients with Alzheimer’s disease and healthy controls: a multicentre phase 2 diagnostic study. Lancet Neurol. 2011;10:424–435. doi: 10.1016/S1474-4422(11)70077-1. [DOI] [PubMed] [Google Scholar]
  • [51].Jin M., Shepardson N., Yang T., Chen G., Walsh D., Selkoe D.J. Soluble amyloid beta-protein dimers isolated from Alzheimer cortex directly induce Tau hyperphosphorylation and neuritic degeneration. Proc Natl Acad Sci U S A. 2011;108:5819–5824. doi: 10.1073/pnas.1017033108. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [52].Zeng K.W., Ko H., Yang H.O., Wang X.M. Icariin attenuates β-amyloid-induced neurotoxicity by inhibition of tau protein hyperphosphorylation in PC12 cells. Neuropharmacology. 2010;59:542–550. doi: 10.1016/j.neuropharm.2010.07.020. [DOI] [PubMed] [Google Scholar]
  • [53].Colangelo V., Schurr J., Ball M.J., Pelaez R.P., Bazan N.G., Lukiw W.J. Gene expression profiling of 12633 genes in Alzheimer hippocampal CA1: transcription and neurotrophic factor down-regulation and up-regulation of apoptotic and proinflammatory signaling. J Neurosci Res. 2002;70:462–473. doi: 10.1002/jnr.10351. [DOI] [PubMed] [Google Scholar]
  • [54].Garzon D., Yu G., Fahnestock M. A new brain-derived neurotrophic factor transcript and decrease in brain-derived neurotrophic factor transcripts 1, 2 and 3 in Alzheimer’s disease parietal cortex. J Neurochem. 2002;82:1058–1064. doi: 10.1046/j.1471-4159.2002.01030.x. [DOI] [PubMed] [Google Scholar]
  • [55].Peng S., Wuu J., Mufson E.J., Fahnestock M. Precursor form of brain-derived neurotrophic factor and mature brainderived neurotrophic factor are decreased in the pre-clinical stages of Alzheimer’s disease. J Neurochem. 2005;93:1412–1421. doi: 10.1111/j.1471-4159.2005.03135.x. [DOI] [PubMed] [Google Scholar]
  • [56].Selkoe DJ. Alzheimer’s disease. Cold Spring Harb Perspect Biol 2011: Epub. [DOI] [PMC free article] [PubMed]
  • [57].Seeman P., Seeman N. Alzheimer’s disease: beta-amyloid plaque formation in human brain. Synapse. 2011;65(12):1289–1297. doi: 10.1002/syn.20957. [DOI] [PubMed] [Google Scholar]
  • [58].Ohyagi Y. Intracellular amyloid beta-protein as a therapeutic target for treating Alzheimer’s disease. Curr Alzheimer Res. 2008;5:555–561. doi: 10.2174/156720508786898514. [DOI] [PubMed] [Google Scholar]
  • [59].Roberson E.D., Mucke L. 100 years and counting: prospects for defeating Alzheimer’s disease. Science. 2006;314:781–784. doi: 10.1126/science.1132813. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [60].West M.J., Coleman P.D., Flood D.G., Troncoso J.C. Differences in the pattern of hippocampal neuronal loss in normal ageing and Alzheimer’s disease. Lancet. 1994;344:769–772. doi: 10.1016/S0140-6736(94)92338-8. [DOI] [PubMed] [Google Scholar]
  • [61].Bobinski M., Wegiel J., Tarnawski M., Bobinski M., Reisberg B., de Leon M.J., et al. Relationships between regional neuronal loss and neurofibrillary changes in the hippocampal formation and duration and severity of Alzheimer disease. J Neuropathol Exp Neurol. 1997;56:414–420. doi: 10.1097/00005072-199704000-00010. [DOI] [PubMed] [Google Scholar]
  • [62].Masliah E., Mallory M., Alford M., DeTeresa R., Hansen L.A., McKeel D.W., Jr, et al. Altered expression of synaptic proteins occurs early during progression of Alzheimer’s disease. Neurology. 2001;56:127–129. doi: 10.1212/WNL.56.1.127. [DOI] [PubMed] [Google Scholar]
  • [63].Capsoni S., Giannotta S., Cattaneo A. Beta-amyloid plaques in a model for sporadic Alzheimer’s disease based on transgenic anti-nerve growth factor antibodies. Mol Cell Neurosci. 2002;21:15–28. doi: 10.1006/mcne.2002.1163. [DOI] [PubMed] [Google Scholar]
  • [64].Houeland G., Romani A., Marchetti C., Amato G., Capsoni S., Cattaneo A., et al. Transgenic mice with chronic NGF deprivation and Alzheimer’s disease-like pathology display hippocampal region-specific impairments in short- and long-term plasticities. J Neurosci. 2010;30:13089–13094. doi: 10.1523/JNEUROSCI.0457-10.2010. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [65].Matrone C., Di Luzio A., Meli G., D’Aguanno S., Severini C., Ciotti M.T., et al. Activation of the amyloidogenic route by NGF deprivation induces apoptotic death in PC12 cells. J Alzheimers Dis. 2008;13:81–96. doi: 10.3233/jad-2008-13109. [DOI] [PubMed] [Google Scholar]
  • [66].Matrone C., Ciotti M.T., Mercanti D., Marolda R., Calissano P. NGF and BDNF signaling control amyloidogenic route and Abeta production in hippocampal neurons. Proc Natl Acad Sci U S A. 2008;105:13139–13144. doi: 10.1073/pnas.0806133105. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [67].Wang Y.J., Wang X., Lu J.J., Li Q.X., Gao C.Y., Liu X.H., et al. p75NTR regulates Abeta deposition by increasing Abeta production but inhibiting Abeta aggregation with its extracellular domain. J Neurosci. 2011;31:2292–2304. doi: 10.1523/JNEUROSCI.2733-10.2011. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [68].Zeng F., Lu J.J., Zhou X.F., Wang Y.J. Roles of p75NTR in the pathogenesis of Alzheimer’s disease: a novel therapeutic target. Biochem Pharmacol. 2011;82:1500–1509. doi: 10.1016/j.bcp.2011.06.040. [DOI] [PubMed] [Google Scholar]
  • [69].Capsoni S., Tiveron C., Vignone D., Amato G., Cattaneo A. Dissecting the involvement of tropomyosin-related kinase A and p75 neurotrophin receptor signaling in NGF deficit-induced neurodegeneration. Proc Natl Acad Sci U S A. 2010;107:12299–12304. doi: 10.1073/pnas.1007181107. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [70].Rinne J.O., Brooks D.J., Rossor M.N., Fox N.C., Bullock R., Klunk W.E., et al. 11C-PiB PET assessment of change in fibrillar amyloid-beta load in patients with Alzheimer’s disease treated with bapineuzumab: a phase 2, double-blind, placebo-controlled, ascending-dose study. Lancet Neurol. 2010;9:363–372. doi: 10.1016/S1474-4422(10)70043-0. [DOI] [PubMed] [Google Scholar]
  • [71].Salloway S., Sperling R., Gilman S., Fox N.C., Blennow K., Raskind M., et al. A phase 2 multiple ascending dose trial of bapineuzumab in mild to moderate Alzheimer disease. Neurology. 2009;73:2061–2070. doi: 10.1212/WNL.0b013e3181c67808. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [72].Holmes C., Boche D., Wilkinson D., Yadegarfar G., Hopkins V., Bayer A., et al. Long-term effects of A beta(42) immunisation in Alzheimer’s disease: follow-up of a randomised, placebocontrolled phase I trial. Lancet. 2008;372:216–223. doi: 10.1016/S0140-6736(08)61075-2. [DOI] [PubMed] [Google Scholar]
  • [73].Imbimbo B.P., Giardina G.A. Gamma-secretase inhibitors and modulators for the treatment of Alzheimer’s disease: disappointments and hopes. Curr Top Med Chem. 2011;11:1555–1570. doi: 10.2174/156802611795860942. [DOI] [PubMed] [Google Scholar]
  • [74].Vellas B. Tarenflurbil for Alzheimer’s disease: a “shot on goal” that missed. Lancet Neurol. 2010;9:235–237. doi: 10.1016/S1474-4422(10)70030-2. [DOI] [PubMed] [Google Scholar]
  • [75].Imbimbo B.P., Panza F., Frisardi V., Solfrizzi V., D’Onofrio G., Logroscino G., et al. Therapeutic intervention for Alzheimer’s disease with gamma-secretase inhibitors: still a viable option? Expert Opin Investig Drugs. 2011;20:325–341. doi: 10.1517/13543784.2011.550572. [DOI] [PubMed] [Google Scholar]
  • [76].Sabbagh M.N. Drug development for Alzheimer’s disease: where are we now and where are we headed? Am J Geriatr Pharmacother. 2009;7:167–185. doi: 10.1016/j.amjopharm.2009.06.003. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [77].D’Alton S, George DR. Changing perspectives on Alzheimer’s disease: thinking outside the amyloid box. J Alzheimers Dis 2011: Epub ahead of print. [DOI] [PubMed]
  • [78].Golde T.E., Petrucelli L., Lewis J. Targeting Abeta and tau in Alzheimer’s disease, an early interim report. Exp Neurol. 2010;223:252–266. doi: 10.1016/j.expneurol.2009.07.035. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [79].Selkoe D.J. Resolving controversies on the path to Alzheimer’s therapeutics. Nat Med. 2011;17:1060–1065. doi: 10.1038/nm.2460. [DOI] [PubMed] [Google Scholar]
  • [80].Geling A., Steiner H., Willem M., Bally-Cuif L., Haass C. A gamma-secretase inhibitor blocks Notch signaling in vivo and causes a severe neurogenic phenotype in zebrafish. EMBO Rep. 2002;3:688–694. doi: 10.1093/embo-reports/kvf124. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [81].Golde T.E., Schneider L.S., Koo E.H. Anti-abeta therapeutics in Alzheimer’s disease: the need for a paradigm shift. Neuron. 2011;69:203–213. doi: 10.1016/j.neuron.2011.01.002. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [82].Lemere C.A., Masliah E. Can Alzheimer disease be prevented by amyloid-beta immunotherapy? Nat Rev Neurol. 2010;6:108–119. doi: 10.1038/nrneurol.2009.219. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [83].Berger Z., Roder H., Hanna A., Carlson A., Rangachari V., Yue M., et al. Accumulation of pathological tau species and memory loss in a conditional model of tauopathy. J Neurosci. 2007;27:3650–3662. doi: 10.1523/JNEUROSCI.0587-07.2007. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [84].Iqbal K., Grundke-Iqbal I., Zaidi T., Merz P.A., Wen G.Y., Shaikh S.S., et al. Defective brain microtubule assembly in Alzheimer’s disease. Lancet. 1986;2:421–426. doi: 10.1016/S0140-6736(86)92134-3. [DOI] [PubMed] [Google Scholar]
  • [85].Liu R., Pei J.J., Wang X.C., Zhou X.W., Tian Q., Winblad B., et al. Acute anoxia induces tau dephosphorylation in rat brain slices and its possible underlying mechanisms. J Neurochem. 2005;94:1225–1234. doi: 10.1111/j.1471-4159.2005.03270.x. [DOI] [PubMed] [Google Scholar]
  • [86].Liu S.J., Zhang A.H., Li H.L., Wang Q., Deng H.M., Netzer W.J., et al. Overactivation of glycogen synthase kinase-3 by inhibition of phosphoinositol-3 kinase and protein kinase C leads to hyperphosphorylation of tau and impairment of spatial memory. J Neurochem. 2003;87:1333–1344. doi: 10.1046/j.1471-4159.2003.02070.x. [DOI] [PubMed] [Google Scholar]
  • [87].Forlenza O.V., Diniz B.S., Radanovic M., Santos F.S., Talib L.L., Gattaz W.F. Disease-modifying properties of long-term lithium treatment for amnestic mild cognitive impairment: randomised controlled trial. Br J Psychiatry. 2011;198:351–356. doi: 10.1192/bjp.bp.110.080044. [DOI] [PubMed] [Google Scholar]
  • [88].Breitner J.C., Baker L.D., Montine T.J., Meinert C.L., Lyketsos C.G., Ashe K.H., et al. Extended results of the Alzheimer’s disease anti-inflammatory prevention trial. Alzheimers Dement. 2011;7:402–411. doi: 10.1016/j.jalz.2010.12.014. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [89].Smith M.A., Rottkamp C.A., Nunomura A., Raina A.K., Perry G. Oxidative stress in Alzheimer’s disease. Biochim Biophys Acta. 2000;1502:139–144. doi: 10.1016/S0925-4439(00)00040-5. [DOI] [PubMed] [Google Scholar]
  • [90].Perry G., Cash A.D., Smith M.A. Alzheimer disease and oxidative stress. J Biomed Biotechnol. 2002;2:120–123. doi: 10.1155/S1110724302203010. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [91].Rutten B.P., Steinbusch H.W., Korr H., Schmitz C. Antioxidants and Alzheimer’s disease: from bench to bedside (and back again) Curr Opin Clin Nutr Metab Care. 2002;5:645–651. doi: 10.1097/00075197-200211000-00006. [DOI] [PubMed] [Google Scholar]
  • [92].Hammarlund M., Nix P., Hauth L., Jorgensen E.M., Bastiani M. Axon regeneration requires a conserved MAP kinase pathway. Science. 2009;323:802–806. doi: 10.1126/science.1165527. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [93].Case L.C., Tessier-Lavigne M. Regeneration of the adult central nervous system. Curr Biol. 2005;15:R749–753. doi: 10.1016/j.cub.2005.09.008. [DOI] [PubMed] [Google Scholar]
  • [94].Yuen E.C., Howe C.L., Li Y., Holtzman D.M., Mobley W.C. Nerve growth factor and the neurotrophic factor hypothesis. Brain Dev. 1996;18:362–368. doi: 10.1016/0387-7604(96)00051-4. [DOI] [PubMed] [Google Scholar]
  • [95].Hu B., Nikolakopoulou A.M., Cohen-Cory S. BDNF stabilizes synapses and maintains the structural complexity of optic axons in vivo. Development. 2005;132:4285–4298. doi: 10.1242/dev.02017. [DOI] [PubMed] [Google Scholar]
  • [96].Grimes M.L., Zhou J., Beattie E.C., Yuen E.C., Hall D.E., Valletta J.S., et al. Endocytosis of activated TrkA: evidence that nerve growth factor induces formation of signaling endosomes. J Neurosci. 1996;16:7950–7964. doi: 10.1523/JNEUROSCI.16-24-07950.1996. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [97].Nagahara A.H., Merrill D.A., Coppola G., Tsukada S., Schroeder B.E., Shaked G.M., et al. Neuroprotective effects of brainderived neurotrophic factor in rodent and primate models of Alzheimer’s disease. Nat Med. 2009;15:331–337. doi: 10.1038/nm.1912. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [98].Fjord-Larsen L., Kusk P., Emerich D.F., Thanos C., Torp M., Bintz B., et al. Increased encapsulated cell biodelivery of nerve growth factor in the brain by transposon-mediated gene transfer. Gene Ther. 2011;19(10):1010–1017. doi: 10.1038/gt.2011.178. [DOI] [PubMed] [Google Scholar]
  • [99].Huang E.J., Reichardt L.F. Neurotrophins: roles in neuronal development and function. Annu Rev Neurosci. 2001;24:677–736. doi: 10.1146/annurev.neuro.24.1.677. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [100].Lin L.F., Xue X.Y., Liao M.J., Xiao F., Lv R.H., Luo H.M. Neurotrophic effects of magnesium fructose 1,6-diphosphate on cortical neurons. Int J Neurosci. 2011;122:248–254. doi: 10.3109/00207454.2011.648291. [DOI] [PubMed] [Google Scholar]
  • [101].Matsui N., Takahashi K., Takeichi M., Kuroshita T., Noguchi K., Yamazaki K., et al. Magnolol and honokiol prevent learning and memory impairment and cholinergic deficit in SAMP8 mice. Brain Res. 2009;1305:108–117. doi: 10.1016/j.brainres.2009.09.107. [DOI] [PubMed] [Google Scholar]
  • [102].Alvarez X.A., Cacabelos R., Sampedro C., Aleixandre M., Linares C., Granizo E., et al. Efficacy and safety of Cerebrolysin in moderate to moderately severe Alzheimer’s disease: results of a randomized, double-blind, controlled trial investigating three dosages of Cerebrolysin. Eur J Neurol. 2011;18:59–68. doi: 10.1111/j.1468-1331.2010.03092.x. [DOI] [PubMed] [Google Scholar]
  • [103].Muresanu DF, Rainer M, Moessler H. Improved global function and activities of daily living in patients with AD: a placebo-controlled clinical study with the neurotrophic agent Cerebrolysin. J Neural Transm Suppl 2002: 277–285. [DOI] [PubMed]
  • [104].Rossler M., Zarski R., Bohl J., Ohm T.G. Stage-dependent and sector-specific neuronal loss in hippocampus during Alzheimer’s disease. Acta Neuropathol. 2002;103:363–369. doi: 10.1007/s00401-001-0475-7. [DOI] [PubMed] [Google Scholar]
  • [105].Scheff S.W., Price D.A., Schmitt F.A., DeKosky S.T., Mufson E.J. Synaptic alterations in CA1 in mild Alzheimer disease and mild cognitive impairment. Neurology. 2007;68:1501–1508. doi: 10.1212/01.wnl.0000260698.46517.8f. [DOI] [PubMed] [Google Scholar]
  • [106].Reiman E.M., Langbaum J.B., Tariot P.N. Alzheimer’s prevention initiative: a proposal to evaluate presymptomatic treatments as quickly as possible. Biomark Med. 2010;4:3–14. doi: 10.2217/bmm.09.91. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [107].Chopra K., Misra S., Kuhad A. Current perspectives on pharmacotherapy of Alzheimer’s disease. Expert Opin Pharmacother. 2011;12:335–350. doi: 10.1517/14656566.2011.520702. [DOI] [PubMed] [Google Scholar]

Articles from Neuroscience Bulletin are provided here courtesy of Springer

RESOURCES