Korean Journal of Biological Psychiatry (생물정신의학)

The Korean Society of Biological Psychiatry (대한생물정신의학회)
권호 표지

Pathogenic Molecular Mechanisms of Glutamatergic Synaptic Proteins in Alzheimer's Disease

알츠하이머 병과 글루타메이트성 시냅스 단백질의 분자적 질환 기전

  • Yang, Jin-Hee (National Creative Research Initiative Center for Synaptogenesis and Department of Biological Sciences, Korea Advanced Institute of Science and Technology(KAIST)) ;
  • Oh, Dae-Young (National Creative Research Initiative Center for Synaptogenesis and Department of Biological Sciences, Korea Advanced Institute of Science and Technology(KAIST))
  • 양진희 (한국과학기술원 생명과학과 시냅스생성 창의연구단, 분자신경생물학연구실) ;
  • 오대영 (한국과학기술원 생명과학과 시냅스생성 창의연구단, 분자신경생물학연구실)
  • Received : 2010.10.15
  • Accepted : 2010.10.25
  • Published : 2010.11.30
Download PDF
⟨ Previous Next ⟩

Abstract

Alzheimer's disease(AD) is the most common neurodegenerative disorder and constitutes about two thirds of dementia. Despite a lot of effort to find drugs for AD worldwide, an efficient medicine that can cure AD has not come yet, which is due to the complicated pathogenic pathways and progressively degenerative properties of AD. In its early clinical phase, it is important to find the subtle alterations in synapses responsible for memory because symptoms of AD patients characteristically start with pure impairment of memory. Attempts to find the target synaptic proteins and their pathogenic pathways will be the most powerful alternative strategy for developing AD medicine. Here we review recent progress in deciphering the role of target synaptic proteins related to AD in hippocampal glutamatergic synapses.

Keywords

References

  1. Querfurth HW, LaFerla FM. Alzheimer's disease. N Engl J Med 2010;362:329-344. https://doi.org/10.1056/NEJMra0909142
  2. Levy-Lahad E, Wasco W, Poorkaj P, Romano DM, Oshima J, Pettingell WH, et al. Candidate gene for the chromosome 1 familial Alzheimer's disease locus. Science 1995;269:973-977. https://doi.org/10.1126/science.7638622
  3. Goate A, Chartier-Harlin MC, Mullan M, Brown J, Crawford F, Fidani L, et al. Segregation of a missense mutation in the amyloid precursor protein gene with familial Alzheimer's disease. Nature 1991;349:704-706. https://doi.org/10.1038/349704a0
  4. Nussbaum RL, Ellis CE. Alzheimer's disease and Parkinson's disease. N Engl J Med 2003;348:1356-1364. https://doi.org/10.1056/NEJM2003ra020003
  5. Corder EH, Saunders AM, Strittmatter WJ, Schmechel DE, Gaskell PC, Small GW, et al. Gene dose of apolipoprotein E type 4 allele and the risk of Alzheimer's disease in late onset families. Science 1993;261:921-923. https://doi.org/10.1126/science.8346443
  6. Brose N, O'Connor V, Skehel P. Synaptopathy: dysfunction of synaptic function? Biochem Soc Trans 2010;38:443-444. https://doi.org/10.1042/BST0380443
  7. Selkoe DJ. Alzheimer's disease is a synaptic failure. Science 2002;298:789-791. https://doi.org/10.1126/science.1074069
  8. Hsieh H, Boehm J, Sato C, Iwatsubo T, Tomita T, Sisodia S, et al. AMPAR removal underlies Abeta-induced synaptic depression and dendritic spine loss. Neuron 2006;52:831-843. https://doi.org/10.1016/j.neuron.2006.10.035
  9. Lacor PN, Buniel MC, Furlow PW, Clemente AS, Velasco PT, Wood M, et al. Abeta oligomer-induced aberrations in synapse composition, shape, and density provide a molecular basis for loss of connectivity in Alzheimer's disease. J Neurosci 2007;27:796-807. https://doi.org/10.1523/JNEUROSCI.3501-06.2007
  10. Opazo P, Choquet D. A three-step model for the synaptic recruitment of AMPA receptors. Mol Cell Neurosci 2010.
  11. Lin YC, Koleske AJ. Mechanisms of synapse and dendrite maintenance and their disruption in psychiatric and neurodegenerative disorders. Annu Rev Neurosci 2010; 33:349-378. https://doi.org/10.1146/annurev-neuro-060909-153204
  12. Sheng M, Kim MJ. Postsynaptic signaling and plasticity mechanisms. Science 2002;298:776-780. https://doi.org/10.1126/science.1075333
  13. Nimchinsky EA, Sabatini BL, Svoboda K. Structure and function of dendritic spines. Annu Rev Physiol 2002;64:313-353. https://doi.org/10.1146/annurev.physiol.64.081501.160008
  14. Tada T, Sheng M. Molecular mechanisms of dendritic spine morphogenesis. Curr Opin Neurobiol 2006;16:95-101. https://doi.org/10.1016/j.conb.2005.12.001
  15. Sheng M, Hoogenraad CC. The postsynaptic architecture of excitatory synapses: a more quantitative view. Annu Rev Biochem 2007;76:823-847. https://doi.org/10.1146/annurev.biochem.76.060805.160029
  16. Baude A, Nusser Z, Roberts JD, Mulvihill E, McIlhinney RA, Somogyi P. The metabotropic glutamate receptor( mGluR1 alpha) is concentrated at perisynaptic membrane of neuronal subpopulations as detected by immunogold reaction. Neuron 1993;11:771-787. https://doi.org/10.1016/0896-6273(93)90086-7
  17. Takumi Y, Ramírez-Leon V, Laake P, Rinvik E, Ottersen OP. Different modes of expression of AMPA and NMDA receptors in hippocampal synapses. Nat Neurosci 1999;2:618-624. https://doi.org/10.1038/10172
  18. Matsuzaki M, Honkura N, Ellis-Davies GC, Kasai H. Structural basis of long-term potentiation in single dendritic spines. Nature 2004;429:761-766. https://doi.org/10.1038/nature02617
  19. Bliss TV, Lomo T. Long-lasting potentiation of synaptic transmission in the dentate area of the anaesthetized rabbit following stimulation of the perforant path. J Physiol 1973;232:331-356. https://doi.org/10.1113/jphysiol.1973.sp010273
  20. Malenka RC, Bear MF. LTP and LTD: an embarrassment of riches. Neuron 2004;44:5-21. https://doi.org/10.1016/j.neuron.2004.09.012
  21. Whitlock JR, Heynen AJ, Shuler MG , Bear MF. Learning induces long-term potentiation in the hippocampus. Science 2006;313:1093-1097. https://doi.org/10.1126/science.1128134
  22. Massey PV, Bashir ZI. Long-term depression: multiple forms and implications for brain function. Trends Neurosci 2007;30:176-184. https://doi.org/10.1016/j.tins.2007.02.005
  23. Selkoe DJ, Schenk D. Alzheimer's disease: molecular understanding predicts amyloid-based therapeutics. Annu Rev Pharmacol Toxicol 2003;43:545-584. https://doi.org/10.1146/annurev.pharmtox.43.100901.140248
  24. Naslund J, Haroutunian V, Mohs R, Davis KL, Davies P, Greengard P, et al. Correlation between elevated levels of amyloid beta-peptide in the brain and cognitive decline. JAMA 2000;283:1571-1577. https://doi.org/10.1001/jama.283.12.1571
  25. DeKosky ST, Scheff SW. Synapse loss in frontal cortex biopsies in Alzheimer's disease: correlation with cognitive severity. Ann Neurol 1990;27:457-464. https://doi.org/10.1002/ana.410270502
  26. McLean CA, Cherny RA, Fraser FW, Fuller SJ, Smith MJ, Beyreuther K, et al. Soluble pool of Abeta amyloid as a determinant of severity of neurodegeneration in Alzheimer's disease. Ann Neurol 1999;46:860-866. https://doi.org/10.1002/1531-8249(199912)46:6<860::AID-ANA8>3.0.CO;2-M
  27. Terry RD, Masliah E, Salmon DP, Butters N, DeTeresa R, Hill R, et al. Physical basis of cognitive alterations in Alzheimer's disease: synapse loss is the major correlate of cognitive impairment. Ann Neurol 1991;30:572-580. https://doi.org/10.1002/ana.410300410
  28. Mucke L, Masliah E, Yu GQ, Mallory M, Rockenstein EM, Tatsuno G, et al. High-level neuronal expression of abeta 1-42 in wild-type human amyloid protein precursor transgenic mice: synaptotoxicity without plaque formation. J Neurosci 2000;20:4050-4058.
  29. Haass C, Selkoe DJ. Soluble protein oligomers in neurodegeneration: lessons from the Alzheimer's amyloid beta- peptide. Nat Rev Mol Cell Biol 2007;8:101-112. https://doi.org/10.1038/nrm2101
  30. Selkoe DJ. Alzheimer's disease: genes, proteins, and therapy. Physiol Rev 2001;81:741-766.
  31. Tanzi RE, Bertram L. Twenty years of the Alzheimer's disease amyloid hypothesis: a genetic perspective. Cell 2005;120:545-555. https://doi.org/10.1016/j.cell.2005.02.008
  32. Walsh DM, Selkoe DJ. A beta oligomers - a decade of discovery. J Neurochem 2007;101:1172-1184. https://doi.org/10.1111/j.1471-4159.2006.04426.x
  33. Kanemitsu H, Tomiyama T, Mori H. Human neprilysin is capable of degrading amyloid beta peptide not only in the monomeric form but also the pathological oligomeric form. Neurosci Lett 2003;350:113-116. https://doi.org/10.1016/S0304-3940(03)00898-X
  34. Iwata N, Tsubuki S, Takaki Y, Shirotani K, Lu B, Gerard NP, et al. Metabolic regulation of brain Abeta by neprilysin. Science 2001;292:1550-1552. https://doi.org/10.1126/science.1059946
  35. Qiu WQ, Walsh DM, Ye Z, Vekrellis K, Zhang J, Podlisny MB, et al. Insulin-degrading enzyme regulates extracellular levels of amyloid beta-protein by degradation. J Biol Chem 1998;273:32730-32738. https://doi.org/10.1074/jbc.273.49.32730
  36. Farris W, Mansourian S, Chang Y, Lindsley L, Eckman EA, Frosch MP, et al. Insulin-degrading enzyme regulates the levels of insulin, amyloid beta-protein, and the beta-amyloid precursor protein intracellular domain in vivo. Proc Natl Acad Sci U S A 2003;100:4162-4167. https://doi.org/10.1073/pnas.0230450100
  37. Kamenetz F, Tomita T, Hsieh H, Seabrook G, Borchelt D, Iwatsubo T, et al. APP processing and synaptic function. Neuron 2003;37:925-937. https://doi.org/10.1016/S0896-6273(03)00124-7
  38. Scheff SW, Price DA, Schmitt FA, DeKosky ST, Mufson EJ. Synaptic alterations in CA1 in mild Alzheimer disease and mild cognitive impairment. Neurology 2007;68:1501-1508. https://doi.org/10.1212/01.wnl.0000260698.46517.8f
  39. Masliah E, Mallory M, Alford M, DeTeresa R, Hansen LA, McKeel DW Jr, et al. Altered expression of synaptic proteins occurs early during progression of Alzheimer's disease. Neurology 2001;56:127-129. https://doi.org/10.1212/WNL.56.1.127
  40. Cullen WK, Suh YH, Anwyl R, Rowan MJ. Block of LTP in rat hippocampus in vivo by beta-amyloid precursor protein fragments. Neuroreport 1997;8:3213-3217. https://doi.org/10.1097/00001756-199710200-00006
  41. Walsh DM, Klyubin I, Fadeeva JV, Cullen WK, Anwyl R, Wolfe MS, et al. Naturally secreted oligomers of amyloid beta protein potently inhibit hippocampal longterm potentiation in vivo. Nature 2002;416:535-539. https://doi.org/10.1038/416535a
  42. Roselli F, Tirard M, Lu J, Hutzler P, Lamberti P, Livrea P, et al. Soluble beta-amyloid1-40 induces NMDA- dependent degradation of postsynaptic density-95 at glutamatergic synapses. J Neurosci 2005;25:11061-11070. https://doi.org/10.1523/JNEUROSCI.3034-05.2005
  43. Zhao D, Watson JB, Xie CW. Amyloid beta prevents activation of calcium/calmodulin-dependent protein kinase II and AMPA receptor phosphorylation during hippocampal long-term potentiation. J Neurophysiol 2004;92:2853-2858. https://doi.org/10.1152/jn.00485.2004
  44. Townsend M, Mehta T, Selkoe DJ. Soluble Abeta inhibits specific signal transduction cascades common to the insulin receptor pathway. J Biol Chem 2007;282:33305-33312. https://doi.org/10.1074/jbc.M610390200
  45. Wei W, Nguyen LN, Kessels HW, Hagiwara H, Sisodia S, Malinow R. Amyloid beta from axons and dendrites reduces local spine number and plasticity. Nat Neurosci 2010;13:190-196. https://doi.org/10.1038/nn.2476
  46. Li S, Hong S, Shepardson NE, Walsh DM, Shankar GM, Selkoe D. Soluble oligomers of amyloid Beta protein facilitate hippocampal long-term depression by disrupting neuronal glutamate uptake. Neuron 2009;62:788-801. https://doi.org/10.1016/j.neuron.2009.05.012
  47. Shankar GM, Bloodgood BL, Townsend M, Walsh DM, Selkoe DJ, Sabatini BL. Natural oligomers of the Alzheimer amyloid-beta protein induce reversible synapse loss by modulating an NMDA-type glutamate receptor- dependent signaling pathway. J Neurosci 2007;27:2866-2875. https://doi.org/10.1523/JNEUROSCI.4970-06.2007
  48. Shankar GM, Li S, Mehta TH, Garcia-Munoz A, Shepardson NE, 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. https://doi.org/10.1038/nm1782
  49. Snyder EM, Nong Y, Almeida CG, Paul S, Moran T, Choi EY, et al. Regulation of NMDA receptor trafficking by amyloid-beta. Nat Neurosci 2005;8:1051-1058. https://doi.org/10.1038/nn1503
  50. Chen QS, Wei WZ, Shimahara T, Xie CW. Alzheimer amyloid beta-peptide inhibits the late phase of long-term potentiation through calcineurin-dependent mechanisms in the hippocampal dentate gyrus. Neurobiol Learn Mem 200;77:354-371. https://doi.org/10.1006/nlme.2001.4034
  51. Shahani N, Brandt R. Functions and malfunctions of the tau proteins. Cell Mol Life Sci 2002;59:1668-1680. https://doi.org/10.1007/PL00012495
  52. Santacruz K, Lewis J, Spires T, Paulson J, Kotilinek L, Ingelsson M, et al. Tau suppression in a neurodegenerative mouse model improves memory function. Science 2005;309:476-481. https://doi.org/10.1126/science.1113694
  53. Oddo S, Vasilevko V, Caccamo A, Kitazawa M, Cribbs DH, LaFerla FM. Reduction of soluble Abeta and tau, but not soluble Abeta alone, ameliorates cognitive decline in transgenic mice with plaques and tangles. J Biol Chem 2006;281:39413-39423. https://doi.org/10.1074/jbc.M608485200
  54. Roberson ED, Scearce-Levie K, Palop JJ, Yan F, Cheng IH, Wu T, et al. Reducing endogenous tau ameliorates amyloid beta-induced deficits in an Alzheimer's disease mouse model. Science 2007;316:750-754. https://doi.org/10.1126/science.1141736
  55. Rapoport M, Dawson HN, Binder LI, Vitek MP, Ferreira A. Tau is essential to beta -amyloid-induced neurotoxicity. Proc Natl Acad Sci U S A 2002;99:6364-6369. https://doi.org/10.1073/pnas.092136199
  56. Oddo S, Billings L, Kesslak JP, Cribbs DH, LaFerla FM. Abeta immunotherapy leads to clearance of early, but not late, hyperphosphorylated tau aggregates via the proteasome. Neuron 2004;43:321-332. https://doi.org/10.1016/j.neuron.2004.07.003
  57. Lewis J, Dickson DW, Lin WL, Chisholm L, Corral A, Jones G, et al. Enhanced neurofibrillary degeneration in transgenic mice expressing mutant tau and APP. Science 2001;293:1487-1491. https://doi.org/10.1126/science.1058189
  58. Iqbal K, Alonso Adel C, Chen S, Chohan MO, El-Akkad E, Gong CX, et al. Tau pathology in Alzheimer disease and other tauopathies. Biochim Biophys Acta 2005;1739:198-210. https://doi.org/10.1016/j.bbadis.2004.09.008
  59. Gong CX, Liu F, Grundke-Iqbal I, Iqbal K. Post-translational modifications of tau protein in Alzheimer's disease. J Neural Transm 2005;112:813-838. https://doi.org/10.1007/s00702-004-0221-0
  60. Ittner LM, Ke YD, Delerue F, Bi M, Gladbach A, van Eersel J, et al. Dendritic function of tau mediates amyloid- beta toxicity in Alzheimer's disease mouse models. Cell 2010;142:387-397. https://doi.org/10.1016/j.cell.2010.06.036
  61. Dickey CA, Dunmore J, Lu B, Wang JW, Lee WC, Kamal A, et al. HSP induction mediates selective clea-rance of tau phosphorylated at proline-directed Ser/Thr sites but not KXGS(MARK)sites. FASEB J 2006;20:753-755. https://doi.org/10.1096/fj.05-5343fje
  62. Myers AJ, Kaleem M, Marlowe L, Pittman AM, Lees AJ, Fung HC, et al. The H1c haplotype at the MAPT locus is associated with Alzheimer's disease. Hum Mol Genet 2005;14:2399-2404. https://doi.org/10.1093/hmg/ddi241
  63. Palop JJ, Chin J, Roberson ED, Wang J, Thwin MT, Bien-Ly N, et al. Aberrant excitatory neuronal activity and compensatory remodeling of inhibitory hippocampal circuits in mouse models of Alzheimer's disease. Neuron 2007;55:697-711. https://doi.org/10.1016/j.neuron.2007.07.025
  64. Palop JJ, Mucke L. Epilepsy and cognitive impairments in Alzheimer disease. Arch Neurol 2009;66:435-440. https://doi.org/10.1001/archneurol.2009.15
  65. Minkeviciene R, Rheims S, Dobszay MB, Zilberter M, Hartikainen J, Fulop L, et al. Amyloid beta-induced neuronal hyperexcitability triggers progressive epilepsy. J Neurosci 2009;29:3453-3462. https://doi.org/10.1523/JNEUROSCI.5215-08.2009
  66. Aarts M, Liu Y, Liu L, Besshoh S, Arundine M, Gurd JW, et al. Treatment of ischemic brain damage by perturbing NMDA receptor- PSD-95 protein interactions. Science 2002;298:846-850. https://doi.org/10.1126/science.1072873
  67. Nakazawa T, Tezuka T, Yamamoto T. [Regulation of NMDA receptor function by Fyn-mediated tyrosine phosphorylation]. Nihon Shinkei Seishin Yakurigaku Zasshi 2002;22:165-167.
  68. Rong Y, Lu X, Bernard A, Khrestchatisky M, Baudry M. Tyrosine phosphorylation of ionotropic glutamate receptors by Fyn or Src differentially modulates their susceptibility to calpain and enhances their binding to spectrin and PSD-95. J Neurochem 2001;79:382-390.
  69. Tezuka T, Umemori H, Akiyama T, Nakanishi S, Yamamoto T. PSD-95 promotes Fyn-mediated tyrosine phosphorylation of the N-methyl-D-aspartate receptor subunit NR2A. Proc Natl Acad Sci U S A 1999;96:435-440. https://doi.org/10.1073/pnas.96.2.435
  70. Chin J, Palop JJ, Puolivali J, Massaro C, Bien-Ly N, Gerstein H, et al. Fyn kinase induces synaptic and cognitive impairments in a transgenic mouse model of Alzheimer's disease. J Neurosci 2005;25:9694-9703. https://doi.org/10.1523/JNEUROSCI.2980-05.2005
  71. Chin J, Palop JJ, Yu GQ, Kojima N, Masliah E, Mucke L. Fyn kinase modulates synaptotoxicity, but not aberrant sprouting, in human amyloid precursor protein transgenic mice. J Neurosci 2004;24:4692-4697. https://doi.org/10.1523/JNEUROSCI.0277-04.2004
  72. Baskys A. Metabotropic receptors and 'slow' excitatory actions of glutamate agonists in the hippocampus. Trends Neurosci 1992;15:92-96. https://doi.org/10.1016/0166-2236(92)90018-4
  73. Nakanishi S. Molecular diversity of glutamate receptors and implications for brain function. Science 1992;258:597-603. https://doi.org/10.1126/science.1329206
  74. Pin JP, Duvoisin R. The metabotropic glutamate receptors: structure and functions. Neuropharmacology 1995;34:1-26. https://doi.org/10.1016/0028-3908(94)00129-G
  75. Bellone C, Luscher C, Mameli M. Mechanisms of synaptic depression triggered by metabotropic glutamate receptors. Cell Mol Life Sci 2008;65:2913-2923. https://doi.org/10.1007/s00018-008-8263-3
  76. Collingridge GL, Peineau S, Howland JG, Wang YT. Long-term depression in the CNS. Nat Rev Neurosci 2010l;11:459-473.
  77. Benarroch EE. Metabotropic glutamate receptors: synaptic modulators and therapeutic targets for neurologic disease. Neurology 2008;70:964-968. https://doi.org/10.1212/01.wnl.0000306315.03021.2a
  78. Wang Q, Walsh DM, Rowan MJ, Selkoe DJ, Anwyl R. Block of long-term potentiation by naturally secreted and synthetic amyloid beta-peptide in hippocampal slices is mediated via activation of the kinases c-Jun N-terminal kinase, cyclin-dependent kinase 5, and p38 mitogen- activated protein kinase as well as metabotropic glutamate receptor type 5. J Neurosci 2004;24:3370-3378. https://doi.org/10.1523/JNEUROSCI.1633-03.2004
  79. Lacor PN, Buniel MC, Chang L, Fernandez SJ, Gong Y, Viola KL, et al. Synaptic targeting by Alzheimer'srelated amyloid beta oligomers. J Neurosci 2004;24:10191-10200. https://doi.org/10.1523/JNEUROSCI.3432-04.2004
  80. Waung MW, Pfeiffer BE, Nosyreva ED, Ronesi JA, Huber KM. Rapid translation of Arc/Arg3.1 selectively mediates mGluR-dependent LTD through persistent increases in AMPAR endocytosis rate. Neuron 2008;59: 84-97. https://doi.org/10.1016/j.neuron.2008.05.014
  81. Bruno V, Copani A, Knopfel T, Kuhn R, Casabona G, Dell'Albani P, et al. Activation of metabotropic glutamate receptors coupled to inositol phospholipid hydrolysis amplifies NMDA-induced neuronal degeneration in cultured cortical cells. Neuropharmacology 1995;34:1089-1098. https://doi.org/10.1016/0028-3908(95)00077-J
  82. Renner M, Lacor PN, Velasco PT, Xu J, Contractor A, Klein WL, et al. Deleterious effects of amyloid beta oligomers acting as an extracellular scaffold for mGlu- R5. Neuron 2010;66:739-754. https://doi.org/10.1016/j.neuron.2010.04.029
  83. Thathiah A, De Strooper B. G protein-coupled receptors, cholinergic dysfunction, and Abeta toxicity in Alzheimer's disease. Sci Signal 2009;2:re8. https://doi.org/10.1126/scisignal.293re8
  84. Xu X. Gamma-secretase catalyzes sequential cleavages of the AbetaPP transmembrane domain. J Alzheimers Dis 2009;16:211-224. https://doi.org/10.3233/JAD-2009-0957
  85. He G, Luo W, Li P, Remmers C, Netzer WJ, Hendrick J, et al. Gamma-secretase activating protein is a therapeutic target for Alzheimer's disease. Nature 2010;467:95-98. https://doi.org/10.1038/nature09325
  86. Ghosh AK, Gemma S, Tang J. beta-Secretase as a therapeutic target for Alzheimer's disease. Neurotherapeutics 2008;5:399-408. https://doi.org/10.1016/j.nurt.2008.05.007
  87. Reddy PH, Beal MF. Amyloid beta, mitochondrial dysfunction and synaptic damage: implications for cognitive decline in aging and Alzheimer's disease. Trends Mol Med 2008;14:45-53. https://doi.org/10.1016/j.molmed.2007.12.002
  88. de la Monte SM, Tong M, Lester-Coll N, Plater M Jr, Wands JR. Therapeutic rescue of neurodegeneration in experimental type 3 diabetes: relevance to Alzheimer's disease. J Alzheimers Dis 2006;10:89-109. https://doi.org/10.3233/JAD-2006-10113
  89. Akiyama H, Barger S, Barnum S, Bradt B, Bauer J, Cole GM, et al. Inflammation and Alzheimer's disease. Neurobiol Aging 2000;21:383-421. https://doi.org/10.1016/S0197-4580(00)00124-X
  90. Lleo A, Berezovska O, Herl L, Raju S, Deng A, Bacskai BJ, et al. Nonsteroidal anti-inflammatory drugs lower Abeta42 and change presenilin 1 conformation. Nat Med 2004;10:1065-1066. https://doi.org/10.1038/nm1112