Learning from the Past: A Review of Clinical Trials Targeting Amyloid, Tau and Neuroinflammation in Alzheimer’s Disease

Author(s): Kelly Ceyzériat, Thomas Zilli, Philippe Millet, Giovanni B. Frisoni, Valentina Garibotto, Benjamin B. Tournier*.

Journal Name: Current Alzheimer Research

Volume 17 , Issue 2 , 2020

  Journal Home
Translate in Chinese
Become EABM
Become Reviewer


Alzheimer’s Disease (AD) is the most common neurodegenerative disease and cause of dementia. Characterized by amyloid plaques and neurofibrillary tangles of hyperphosphorylated Tau, AD pathology has been intensively studied during the last century. After a long series of failed trials of drugs targeting amyloid or Tau deposits, currently, hope lies in the positive results of one Phase III trial, highly debated, and on other ongoing trials. In parallel, some approaches target neuroinflammation, another central feature of AD. Therapeutic strategies are initially evaluated on animal models, in which the various drugs have shown effects on the target (decreasing amyloid, Tau and neuroinflammation) and sometimes on cognitive impairment. However, it is important to keep in mind that rodent models have a less complex brain than humans and that the pathology is generally not fully represented. Although they are indispensable tools in the drug discovery process, results obtained from animal models must be viewed with caution. In this review, we focus on the current status of disease-modifying therapies targeting amyloid, Tau and neuroinflammation with particular attention on the discrepancy between positive preclinical results on animal models and failures in clinical trials.

Keywords: Alzheimer’s disease, therapies, amyloid load, tau, neuroinflammation, animal models.

Livingston G, Sommerlad A, Orgeta V, et al. Dementia prevention, intervention, and care. Lancet 390(10113): 2673-734. (2017).
[http://dx.doi.org/10.1016/S0140-6736(17)31363-6] [PMID: 28735855]
Blennow K, de Leon MJ, Zetterberg H. Alzheimer’s disease. Lancet 368(9533): 387-403. (2006).
[http://dx.doi.org/10.1016/S0140-6736(06)69113-7] [PMID: 16876668]
Ardura-Fabregat A, Boddeke EWGM, Boza-Serrano A, et al. Targeting neuroinflammation to treat Alzheimer’s disease. CNS Drugs 31(12): 1057-82. (2017).
[http://dx.doi.org/10.1007/s40263-017-0483-3] [PMID: 29260466]
Goate A, Chartier-Harlin MC, Mullan M, et al. Segregation of a missense mutation in the amyloid precursor protein gene with familial Alzheimer’s disease. Nature 349(6311): 704-6. (1991).
[http://dx.doi.org/10.1038/349704a0] [PMID: 1671712]
Levy-Lahad E, Wasco W, Poorkaj P, et al. Candidate gene for the chromosome 1 familial Alzheimer’s disease locus. Science 269(5226): 973-7. (1995).
[http://dx.doi.org/10.1126/science.7638622] [PMID: 7638622]
Schellenberg GD, Bird TD, Wijsman EM, et al. Genetic linkage evidence for a familial Alzheimer’s disease locus on chromosome 14. Science 258(5082): 668-71. (1992).
[http://dx.doi.org/10.1126/science.1411576] [PMID: 1411576]
Hardy JA, Higgins GA. Alzheimer’s disease: the amyloid cascade hypothesis. Science 256(5054): 184-5. (1992).
[http://dx.doi.org/10.1126/science.1566067] [PMID: 1566067]
Thal DR, Griffin WST, de Vos RAI, Ghebremedhin E. Cerebral amyloid angiopathy and its relationship to Alzheimer’s disease. Acta Neuropathol 115(6): 599-609. (2008).
[http://dx.doi.org/10.1007/s00401-008-0366-2] [PMID: 18369648]
Barbier P, Zejneli O, Martinho M, et al. Role of tau as a microtubule-associated protein: structural and functional aspects. Front Aging Neurosci 11: 204. (2019).
[http://dx.doi.org/10.3389/fnagi.2019.00204] [PMID: 31447664]
Braak H, Braak E. Neuropathological stageing of Alzheimer-related changes. Acta Neuropathol 82(4): 239-59. (1991).
[http://dx.doi.org/10.1007/BF00308809] [PMID: 1759558]
Masters CL, Bateman R, Blennow K, Rowe CC, Sperling RA, Cummings JL. Alzheimer’s disease. Nat Rev Dis Primers 1: 15056. (2015).
[http://dx.doi.org/10.1038/nrdp.2015.56] [PMID: 27188934]
Hamelin L, Lagarde J, Dorothée G, et al. Early and protective microglial activation in Alzheimer’s disease: a prospective study using 18F-DPA-714 PET imaging. Brain 139(Pt 4): 1252-64. (2016).
[http://dx.doi.org/10.1093/brain/aww017] [PMID: 26984188]
Carter SF, Schöll M, Almkvist O, et al. Evidence for astrocytosis in prodromal Alzheimer disease provided by 11C-deuterium-L-deprenyl: a multitracer PET paradigm combining 11C-Pittsburgh compound B and 18F-FDG. J Nucl Med 53(1): 37-46. (2012).
Rodriguez-Vieitez E, Saint-Aubert L, Carter SF, et al. Diverging longitudinal changes in astrocytosis and amyloid PET in autosomal dominant Alzheimer’s disease. Brain 139(Pt 3): 922-36. (2016).
[http://dx.doi.org/10.1093/brain/awv404] [PMID: 26813969]
Schliebs R, Arendt T. The significance of the cholinergic system in the brain during aging and in Alzheimer’s disease. J Neural Transm (Vienna) 113(11): 1625-44. (2006).
[http://dx.doi.org/10.1007/s00702-006-0579-2] [PMID: 17039298]
Birks J. Cholinesterase inhibitors for Alzheimer’s disease. Cochrane Database Syst Rev (1): : CD005593 (2006).
[PMID: 16437532]
Nyakas C, Granic I, Halmy LG, Banerjee P, Luiten PGM. The basal forebrain cholinergic system in aging and dementia. Rescuing cholinergic neurons from neurotoxic amyloid-β42 with memantine. Behav Brain Res 221(2): 594-603. (2011).
[http://dx.doi.org/10.1016/j.bbr.2010.05.033] [PMID: 20553766]
van Marum RJ. Update on the use of memantine in Alzheimer’s disease. Neuropsychiatr Dis Treat 5: 237-47. (2009).
[http://dx.doi.org/10.2147/NDT.S4048] [PMID: 19557118]
Gauthier S, Loft H, Cummings J. Improvement in behavioural symptoms in patients with moderate to severe Alzheimer’s disease by memantine: a pooled data analysis. Int J Geriatr Psychiatry 23(5): 537-45. (2008).
[http://dx.doi.org/10.1002/gps.1949] [PMID: 18058838]
Reisberg B, Doody R, Stöffler A, Schmitt F, Ferris S, Möbius HJ. Memantine in moderate-to-severe Alzheimer’s disease. N Engl J Med 348(14): 1333-41. (2003).
[http://dx.doi.org/10.1056/NEJMoa013128] [PMID: 12672860]
Schenk D, Barbour R, Dunn W, et al. Immunization with amyloid-beta attenuates Alzheimer-disease-like pathology in the PDAPP mouse. Nature 400(6740): 173-7. (1999).
[http://dx.doi.org/10.1038/22124] [PMID: 10408445]
Janus C, Pearson J, McLaurin J, et al. A beta peptide immunization reduces behavioural impairment and plaques in a model of Alzheimer’s disease. Nature 408(6815): 979-82. (2000).
[http://dx.doi.org/10.1038/35050110] [PMID: 11140685]
Gilman S, Koller M, Black RS, et al. Clinical effects of Abeta immunization (AN1792) in patients with AD in an interrupted trial. Neurology 64(9): 1553-62. (2005).
[http://dx.doi.org/10.1212/01.WNL.0000159740.16984.3C] [PMID: 15883316]
Nicoll JAR, Wilkinson D, Holmes C, Steart P, Markham H, Weller RO. Neuropathology of human Alzheimer disease after immunization with amyloid-beta peptide: a case report. Nat Med 9(4): 448-52. (2003).
[http://dx.doi.org/10.1038/nm840] [PMID: 12640446]
Ferrer I, Boada Rovira M, Sánchez Guerra ML, Rey MJ, Costa-Jussá F. Neuropathology and pathogenesis of encephalitis following amyloid-beta immunization in Alzheimer’s disease. Brain Pathol 14(1): 11-20. (2004).
[http://dx.doi.org/10.1111/j.1750-3639.2004.tb00493.x] [PMID: 14997933]
Masliah E, Hansen L, Adame A, et al. Abeta vaccination effects on plaque pathology in the absence of encephalitis in Alzheimer disease. Neurology 64(1): 129-31. (2005).
[http://dx.doi.org/10.1212/01.WNL.0000148590.39911.DF] [PMID: 15642916]
Nicoll JAR, Buckland GR, Harrison CH, et al. Persistent neuropathological effects 14 years following amyloid-β immunization in Alzheimer’s disease. Brain 142(7): 2113-26. (2019).
[http://dx.doi.org/10.1093/brain/awz142] [PMID: 31157360]
Bard F, Cannon C, Barbour R, et al. Peripherally administered antibodies against amyloid beta-peptide enter the central nervous system and reduce pathology in a mouse model of Alzheimer disease. Nat Med 6(8): 916-9. (2000).
[http://dx.doi.org/10.1038/78682] [PMID: 10932230]
Kotilinek LA, Bacskai B, Westerman M, et al. Reversible memory loss in a mouse transgenic model of Alzheimer’s disease. J Neurosci 22(15): 6331-5. (2002).
[http://dx.doi.org/10.1523/JNEUROSCI.22-15-06331.2002] [PMID: 12151510]
Salloway S, Sperling R, Fox NC, et al. Two phase 3 trials of bapineuzumab in mild-to-moderate Alzheimer’s disease. N Engl J Med 370(4): 322-33. (2014).
[http://dx.doi.org/10.1056/NEJMoa1304839] [PMID: 24450891]
Siemers ER, Sundell KL, Carlson C, et al. Phase 3 solanezumab trials: Secondary outcomes in mild Alzheimer’s disease patients. Alzheimers Dement 12(2): 110-20. (2016).
[http://dx.doi.org/10.1016/j.jalz.2015.06.1893] [PMID: 26238576]
Honig LS, Vellas B, Woodward M, et al. Trial of solanezumab for mild dementia due to Alzheimer’s disease. N Engl J Med 378(4): 321-30. (2018).
[http://dx.doi.org/10.1056/NEJMoa1705971] [PMID: 29365294]
Panza F, Seripa D, Lozupone M, et al. The potential of solanezumab and gantenerumab to prevent Alzheimer’s disease in people with inherited mutations that cause its early onset. Expert Opin Biol Ther 18(1): 25-35. (2018).
[http://dx.doi.org/10.1080/14712598.2018.1389885] [PMID: 29037101]
Sevigny J, Chiao P, Bussière T, et al. The antibody aducanumab reduces Aβ plaques in Alzheimer’s disease. Nature 537(7618): 50-6. (2016).
[http://dx.doi.org/10.1038/nature19323] [PMID: 27582220]
Biogen and Eisai to Discontinue Phase 3 ENGAGE and EMERGE Trials of aducanumab in Alzheimer’s Disease. http://investors. biogen.com/news-releases/news-release-details/biogen-and-eisai-discontinue-phase-3-engage-and-emerge-trials
Schneider L. A resurrection of aducanumab for Alzheimer’s disease. Lancet Neurol 19(2): 111-2. (2020).
[PMID: 31978357]
Luo Y, Bolon B, Kahn S, et al. Mice deficient in BACE1, the Alzheimer’s beta-secretase, have normal phenotype and abolished beta-amyloid generation. Nat Neurosci 4(3): 231-2. (2001).
[http://dx.doi.org/10.1038/85059] [PMID: 11224535]
Kennedy ME, Stamford AW, Chen X, et al. The BACE1 inhibitor verubecestat (MK-8931) reduces CNS β-amyloid in animal models and in Alzheimer’s disease patients. Sci Transl Med 8(363): 363ra150 (2016).
[http://dx.doi.org/10.1126/scitranslmed.aad9704] [PMID: 27807285]
Egan MF, Kost J, Tariot PN, et al. Randomized trial of verubecestat for mild-to-moderate Alzheimer’s disease. N Engl J Med 378(18): 1691-703. (2018).
[http://dx.doi.org/10.1056/NEJMoa1706441] [PMID: 29719179]
Merck announces discontinuation of apecs study evaluating verubecestat (mk-8931) for the treatment of people with prodromal Alzheimer’s disease | Merck Newsroom Home, Available from: https://www.mrknewsroom.com/news-release/research-and-development-news/merck-announces-discontinuation-apecs-study-evaluating-ve
Wessels AM, Tariot PN, Zimmer JA, et al. Efficacy and safety of lanabecestat for treatment of early and mild Alzheimer disease: The AMARANTH and DAYBREAK-ALZ randomized clinical trials. JAMA Neurol 77(2): 199-209. (2019).
[PMID: 31764959]
Novartis, Amgen and Banner Alzheimer’s Institute discontinue clinical program with BACE inhibitor CNP520 for Alzheimer’s prevention, Available from: https://www.novartis.com/news/media-releases/novartis-amgen-and-banner-alzheimers-institute-discontinue-clinical- program-bace-inhibitor-cnp520-alzheimers-prevention
Wong GT, Manfra D, Poulet FM, et al. Chronic treatment with the gamma-secretase inhibitor LY-411,575 inhibits beta-amyloid peptide production and alters lymphopoiesis and intestinal cell differentiation. J Biol Chem 279(13): 12876-82. (2004).
[http://dx.doi.org/10.1074/jbc.M311652200] [PMID: 14709552]
Milano J, McKay J, Dagenais C, et al. Modulation of notch processing by gamma-secretase inhibitors causes intestinal goblet cell metaplasia and induction of genes known to specify gut secretory lineage differentiation. Toxicol Sci 82(1): 341-58. (2004).
[http://dx.doi.org/10.1093/toxsci/kfh254] [PMID: 15319485]
Penninkilampi R, Brothers HM, Eslick GD. Pharmacological agents targeting γ-secretase increase risk of cancer and cognitive decline in Alzheimer’s disease patients: a systematic review and meta-analysis. J Alzheimers Dis 53(4): 1395-404. (2016).
[http://dx.doi.org/10.3233/JAD-160275] [PMID: 27392862]
Etcheberrigaray R, Tan M, Dewachter I, et al. Therapeutic effects of PKC activators in Alzheimer’s disease transgenic mice. Proc Natl Acad Sci USA 101(30): 11141-6. (2004).
[http://dx.doi.org/10.1073/pnas.0403921101] [PMID: 15263077]
Farlow MR, Thompson RE, Wei L-J, et al. A randomized, double-blind, placebo-controlled, phase II study assessing safety, tolerability, and efficacy of bryostatin in the treatment of moderately severe to severe Alzheimer’s disease. J Alzheimers Dis 67(2): 555-70. (2019).
[http://dx.doi.org/10.3233/JAD-180759] [PMID: 30530975]
Crouch PJ, Savva MS, Hung LW, et al. The Alzheimer’s therapeutic PBT2 promotes amyloid-β degradation and GSK3 phosphorylation via a metal chaperone activity. J Neurochem 119(1): 220-30. (2011).
[http://dx.doi.org/10.1111/j.1471-4159.2011.07402.x] [PMID: 21797865]
Adlard PA, Bica L, White AR, et al. Metal ionophore treatment restores dendritic spine density and synaptic protein levels in a mouse model of Alzheimer’s disease. PLoS One 6(3): e17669 (2011).
[http://dx.doi.org/10.1371/journal.pone.0017669] [PMID: 21412423]
Lannfelt L, Blennow K, Zetterberg H, et al. Safety, efficacy, and biomarker findings of PBT2 in targeting Abeta as a modifying therapy for Alzheimer’s disease: a phase IIa, double-blind, randomised, placebo-controlled trial. Lancet Neurol 7(9): 779-86. (2008).
[http://dx.doi.org/10.1016/S1474-4422(08)70167-4] [PMID: 18672400]
Villemagne VL, Rowe CC, Barnham KJ, et al. A randomized, exploratory molecular imaging study targeting amyloid β with a novel 8-OH quinoline in Alzheimer’s disease: The PBT2-204 IMAGINE study. Alzheimers Dement (N Y) 3(4): 622-35. (2017).
[http://dx.doi.org/10.1016/j.trci.2017.10.001] [PMID: 29201996]
Kametani F, Hasegawa M. Reconsideration of amyloid hypothesis and tau hypothesis in Alzheimer’s disease. Front Neurosci 12: 25. (2018).
[http://dx.doi.org/10.3389/fnins.2018.00025] [PMID: 29440986]
Jadhav S, Avila J, Schöll M, et al. A walk through tau therapeutic strategies. Acta Neuropathol Commun 7(1): 22. (2019).
[http://dx.doi.org/10.1186/s40478-019-0664-z] [PMID: 30767766]
Yanamandra K, Kfoury N, Jiang H, et al. Anti-tau antibodies that block tau aggregate seeding in vitro markedly decrease pathology and improve cognition in vivo. Neuron 80(2): 402-14. (2013).
[http://dx.doi.org/10.1016/j.neuron.2013.07.046] [PMID: 24075978]
Congdon EE, Lin Y, Rajamohamedsait HB, et al. Affinity of Tau antibodies for solubilized pathological Tau species but not their immunogen or insoluble Tau aggregates predicts in vivo and ex vivo efficacy. Mol Neurodegener 11(1): 62. (2016).
[http://dx.doi.org/10.1186/s13024-016-0126-z] [PMID: 27578006]
Sigurdsson EM. Tau immunotherapies for Alzheimer’s disease and related tauopathies: progress and potential pitfalls. J Alzheimers Dis 64(s1): S555-65. (2018).
[http://dx.doi.org/10.3233/JAD-179937] [PMID: 29865056]
Theunis C, Crespo-Biel N, Gafner V, et al. Efficacy and safety of a liposome-based vaccine against protein Tau, assessed in tau.P301L mice that model tauopathy. PLoS One 8(8): e72301 (2013).
[http://dx.doi.org/10.1371/journal.pone.0072301] [PMID: 23977276]
AC Immune Initiates Ph1b/2a Study of Anti-Phospho-Tau Vaccine in Alzheimer’s Disease, Available from: http://www.globenewswire. com/news-release/2019/08/01/1895428/0/en/AC-Immune-Initiates-Ph1b-2a-Study-of-Anti-Phospho-Tau-Vaccine-in-Alzheimer-s-Disease.html
Kontsekova E, Zilka N, Kovacech B, Novak P, Novak M. First-in-man tau vaccine targeting structural determinants essential for pathological tau-tau interaction reduces tau oligomerisation and neurofibrillary degeneration in an Alzheimer’s disease model. Alzheimers Res Ther 6(4): 44. (2014).
[http://dx.doi.org/10.1186/alzrt278] [PMID: 25478017]
Yanamandra K, Jiang H, Mahan TE, et al. Anti-tau antibody reduces insoluble tau and decreases brain atrophy. Ann Clin Transl Neurol 2(3): 278-88. (2015).
[http://dx.doi.org/10.1002/acn3.176] [PMID: 25815354]
Alam R, Driver D, Wu S, Lozano E, Key SL, Hole JT, et al. Preclinical characterization of an antibody [LY3303560] targeting aggregated Tau. Alzheimers Dement 13(7)(Suppl.): 592-P593. (2017).
Czerkowicz J, Chen W, Cameron A, Sopko R, Weinreb P, Hering H, et al. Anti-tau antibody BIIB092 binds secreted tau in preclinical models and alzheimer’s disease cerebrospinal fluid. Alzheimers Dement 14(7): 1441. (2018).
Czerkowicz J, Chen W, Wang Q, Shen C, Wager C, Stone I, et al. Pan-Tau antibody Biib076 exhibits promising safety and biomarker profile in cynomolgus monkey toxicity study. Alzheimers Dement 13(7): 1271. (2017).
Zhang Y, Tian Q, Zhang Q, Zhou X, Liu S, Wang J-Z. Hyperphosphorylation of microtubule-associated tau protein plays dual role in neurodegeneration and neuroprotection. Pathophysiology 16(4): 311-6. (2009).
[http://dx.doi.org/10.1016/j.pathophys.2009.02.003] [PMID: 19410438]
Derisbourg M, Leghay C, Chiappetta G, et al. Role of the Tau N-terminal region in microtubule stabilization revealed by new endogenous truncated forms. Sci Rep 5: 9659. (2015).
[http://dx.doi.org/10.1038/srep09659] [PMID: 25974414]
Qiang L, Sun X, Austin TO, et al. Tau does not stabilize axonal microtubules but rather enables them to have long labile domains. Curr Biol 28(13): 2181-2189.e4. (2018).
[http://dx.doi.org/10.1016/j.cub.2018.05.045] [PMID: 30008334]
Hernández F, García-García E, Avila J. Microtubule depolymerization and tau phosphorylation. J Alzheimers Dis 37(3): 507-13. (2013).
[http://dx.doi.org/10.3233/JAD-130545] [PMID: 23948896]
Xia Y, Sorrentino ZA, Kim JD, Strang KH, Riffe CJ, Giasson BI. Impaired tau-microtubule interactions are prevalent among pathogenic tau variants arising from missense mutations. J Biol Chem 294(48): 18488-503. (2019).
[http://dx.doi.org/10.1074/jbc.RA119.010178] [PMID: 31653695]
Tsai RM, Miller Z, Koestler M, et al. Reactions to Multiple ascending doses of the microtubule stabilizer TPI-287 in patients with alzheimer disease, progressive supranuclear palsy, and corticobasal syndrome: a randomized clinical trial. JAMA Neurol 77(2): 215-24. (2019).
[PMID: 31710340]
Serenó L, Coma M, Rodríguez M, et al. A novel GSK-3beta inhibitor reduces Alzheimer’s pathology and rescues neuronal loss in vivo. Neurobiol Dis 35(3): 359-67. (2009).
[http://dx.doi.org/10.1016/j.nbd.2009.05.025] [PMID: 19523516]
del Ser T, Steinwachs KC, Gertz HJ, et al. Treatment of Alzheimer’s disease with the GSK-3 inhibitor tideglusib: a pilot study. J Alzheimers Dis 33(1): 205-15. (2013).
[http://dx.doi.org/10.3233/JAD-2012-120805] [PMID: 22936007]
Lovestone S, Boada M, Dubois B, et al. A phase II trial of tideglusib in Alzheimer’s disease. J Alzheimers Dis 45(1): 75-88. (2015).
[http://dx.doi.org/10.3233/JAD-141959] [PMID: 25537011]
Congdon EE, Sigurdsson EM. Tau-targeting therapies for Alzheimer disease. Nat Rev Neurol 14(7): 399-415. (2018).
[http://dx.doi.org/10.1038/s41582-018-0013-z] [PMID: 29895964]
Sun W, Lee S, Huang X, et al. Attenuation of synaptic toxicity and MARK4/PAR1-mediated Tau phosphorylation by methylene blue for Alzheimer’s disease treatment. Sci Rep 6: 34784. (2016).
[http://dx.doi.org/10.1038/srep34784] [PMID: 27708431]
Medina DX, Caccamo A, Oddo S. Methylene blue reduces aβ levels and rescues early cognitive deficit by increasing proteasome activity. Brain Pathol 21(2): 140-9. (2011).
[http://dx.doi.org/10.1111/j.1750-3639.2010.00430.x] [PMID: 20731659]
Schelter BO, Shiells H, Baddeley TC, et al. Concentration-dependent activity of hydromethyl-thionine on cognitive decline and brain atrophy in mild to moderate Alzheimer’s disease. J Alzheimers Dis 72(3): 931-46. (2019).
[http://dx.doi.org/10.3233/JAD-190772] [PMID: 31658058]
Calsolaro V, Edison P. Neuroinflammation in Alzheimer’s disease: Current evidence and future directions. Alzheimers Dement 12(6): 719-32. (2016).
[http://dx.doi.org/10.1016/j.jalz.2016.02.010] [PMID: 27179961]
López González I, Garcia-Esparcia P, Llorens F, Ferrer I. Genetic and transcriptomic profiles of inflammation in neurodegenerative diseases: Alzheimer, Parkinson, Creutzfeldt-Jakob and Tauopathies. Int J Mol Sci 17(2): 206. (2016).
[http://dx.doi.org/10.3390/ijms17020206] [PMID: 26861289]
Corder EH, Saunders AM, Strittmatter WJ, et al. Gene dose of apolipoprotein E type 4 allele and the risk of Alzheimer’s disease in late onset families. Science 261(5123): 921-3. (1993).
[http://dx.doi.org/10.1126/science.8346443] [PMID: 8346443]
Bu G. Apolipoprotein E and its receptors in Alzheimer’s disease: pathways, pathogenesis and therapy. Nat Rev Neurosci 10(5): 333-44. (2009).
[http://dx.doi.org/10.1038/nrn2620] [PMID: 19339974]
Guerreiro R, Wojtas A, Bras J, et al. TREM2 variants in Alzheimer’s disease. N Engl J Med 368(2): 117-27. (2013).
[http://dx.doi.org/10.1056/NEJMoa1211851] [PMID: 23150934]
Jonsson T, Stefansson H, Steinberg S, et al. Variant of TREM2 associated with the risk of Alzheimer’s disease. N Engl J Med 368(2): 107-16. (2013).
[http://dx.doi.org/10.1056/NEJMoa1211103] [PMID: 23150908]
Tournier BB, Tsartsalis S, Rigaud D, et al. TSPO and amyloid deposits in sub-regions of the hippocampus in the 3xTgAD mouse model of Alzheimer’s disease. Neurobiol Dis 121: 95-105. (2019).
[http://dx.doi.org/10.1016/j.nbd.2018.09.022] [PMID: 30261283]
Chaney A, Williams SR, Boutin H. In vivo molecular imaging of neuroinflammation in Alzheimer’s disease. J Neurochem 149(4): 438-51. (2019).
[http://dx.doi.org/10.1111/jnc.14615] [PMID: 30339715]
Aisen PS. The potential of anti-inflammatory drugs for the treatment of Alzheimer’s disease. Lancet Neurol 1(5): 279-84. (2002).
[http://dx.doi.org/10.1016/S1474-4422(02)00133-3] [PMID: 12849425]
Eriksen JL, Sagi SA, Smith TE, et al. NSAIDs and enantiomers of flurbiprofen target gamma-secretase and lower Abeta 42 in vivo. J Clin Invest 112(3): 440-9. (2003).
[http://dx.doi.org/10.1172/JCI18162] [PMID: 12897211]
Jaturapatporn D, Isaac MGEKN, McCleery J, Tabet N. Aspirin, steroidal and non-steroidal anti-inflammatory drugs for the treatment of Alzheimer’s disease. Cochrane Database Syst Rev (2): : CD006378 (2012).
[http://dx.doi.org/10.1002/14651858.CD006378.pub2] [PMID: 22336816]
Alam JJ. Selective brain-targeted antagonism of p38 MAPKα reduces hippocampal IL-1β levels and improves morris water maze performance in aged rats. J Alzheimers Dis 48(1): 219-27. (2015).
[http://dx.doi.org/10.3233/JAD-150277] [PMID: 26401942]
Scheltens P, Prins N, Lammertsma A, et al. An exploratory clinical study of p38α kinase inhibition in Alzheimer’s disease. Ann Clin Transl Neurol 5(4): 464-73. (2018).
[http://dx.doi.org/10.1002/acn3.549] [PMID: 29687023]
Murphy MP, LeVine H III. Alzheimer’s disease and the amyloid-β peptide. J Alzheimers Dis 19(1): 311-23. (2010).
[http://dx.doi.org/10.3233/JAD-2010-1221] [PMID: 20061647]
Marquié M, Normandin MD, Vanderburg CR, et al. Validating novel tau positron emission tomography tracer [F-18]-AV-1451 (T807) on postmortem brain tissue. Ann Neurol 78(5): 787-800. (2015).
[http://dx.doi.org/10.1002/ana.24517] [PMID: 26344059]
DeTure M, Ko L-W, Easson C, Yen S-H. Tau assembly in inducible transfectants expressing wild-type or FTDP-17 tau. Am J Pathol 161(5): 1711-22. (2002).
[http://dx.doi.org/10.1016/S0002-9440(10)64448-3] [PMID: 12414518]
Chang E, Kim S, Yin H, Nagaraja HN, Kuret J. Pathogenic missense MAPT mutations differentially modulate tau aggregation propensity at nucleation and extension steps. J Neurochem 107(4): 1113-23. (2008).
[PMID: 18803694]
Duyckaerts C, Potier MC, Delatour B. Alzheimer disease models and human neuropathology: similarities and differences. Acta Neuropathol 115(1): 5-38. (2008).
[http://dx.doi.org/10.1007/s00401-007-0312-8] [PMID: 18038275]
Radde R, Bolmont T, Kaeser SA, et al. Abeta42-driven cerebral amyloidosis in transgenic mice reveals early and robust pathology. EMBO Rep 7(9): 940-6. (2006).
[http://dx.doi.org/10.1038/sj.embor.7400784] [PMID: 16906128]
Herculano-Houzel S. The human brain in numbers: a linearly scaled-up primate brain. Front Hum Neurosci 3: 31. (2009).
[http://dx.doi.org/10.3389/neuro.09.031.2009] [PMID: 19915731]
Herculano-Houzel S. The glia/neuron ratio: how it varies uniformly across brain structures and species and what that means for brain physiology and evolution. Glia 62(9): 1377-91. (2014).
[http://dx.doi.org/10.1002/glia.22683] [PMID: 24807023]
Cohen RM, Rezai-Zadeh K, Weitz TM, et al. A transgenic Alzheimer rat with plaques, tau pathology, behavioral impairment, oligomeric aβ, and frank neuronal loss. J Neurosci 33(15): 6245-56. (2013).
[http://dx.doi.org/10.1523/JNEUROSCI.3672-12.2013] [PMID: 23575824]
Sebastián-Serrano Á, de Diego-García L, Díaz-Hernández M. The neurotoxic role of extracellular tau protein. Int J Mol Sci 19(4): E998 (2018).
[http://dx.doi.org/10.3390/ijms19040998] [PMID: 29584657]
Tsartsalis S, Xekardaki A, Hof PR, Kövari E, Bouras C. Early Alzheimer-type lesions in cognitively normal subjects. Neurobiol Aging 62: 34-44. (2018).
[http://dx.doi.org/10.1016/j.neurobiolaging.2017.10.002] [PMID: 29107845]
Peters F, Salihoglu H, Pratsch K, et al. Tau deletion reduces plaque-associated BACE1 accumulation and decelerates plaque formation in a mouse model of Alzheimer’s disease. EMBO J 38(23): e102345 (2019).
[http://dx.doi.org/10.15252/embj.2019102345] [PMID: 31701556]
Jagust W. Tau and β-amyloid-the malignant duo. JAMA Neurol 73(9): 1049-50. (2016).
[http://dx.doi.org/10.1001/jamaneurol.2016.2481] [PMID: 27454015]
Wang L, Benzinger TL, Su Y, et al. Evaluation of tau imaging in staging Alzheimer disease and revealing interactions between β-amyloid and tauopathy. JAMA Neurol 73(9): 1070-7. (2016).
[http://dx.doi.org/10.1001/jamaneurol.2016.2078] [PMID: 27454922]
Rodriguez-Vieitez E, Ni R, Gulyás B, et al. Astrocytosis precedes amyloid plaque deposition in Alzheimer APPswe transgenic mouse brain: a correlative positron emission tomography and in vitro imaging study. Eur J Nucl Med Mol Imaging 42(7): 1119-32. (2015).
[http://dx.doi.org/10.1007/s00259-015-3047-0] [PMID: 25893384]
Löffler T, Flunkert S, Havas D, et al. Neuroinflammation and related neuropathologies in APPSL mice: further value of this in vivo model of Alzheimer’s disease. J Neuroinflammation 11: 84. (2014).
[http://dx.doi.org/10.1186/1742-2094-11-84] [PMID: 24886182]
Ben Haim L, Carrillo-de Sauvage MA, Ceyzériat K, Escartin C. Elusive roles for reactive astrocytes in neurodegenerative diseases. Front Cell Neurosci 9: 278. (2015).
[http://dx.doi.org/10.3389/fncel.2015.00278] [PMID: 26283915]
Sarlus H, Heneka MT. Microglia in Alzheimer’s disease. J Clin Invest 127(9): 3240-9. (2017).
[http://dx.doi.org/10.1172/JCI90606] [PMID: 28862638]

Rights & PermissionsPrintExport Cite as

Article Details

Year: 2020
Page: [112 - 125]
Pages: 14
DOI: 10.2174/1567205017666200304085513
Price: $65

Article Metrics

PDF: 28