Alzheimer’s Association. 2015 Alzheimer’s disease facts and figures. Alzheimers Dement. 2015;11:332–84.
Glenner GG, Wong CW. Alzheimer’s disease: initial report of the purification and characterization of a novel cerebrovascular amyloid protein. Biochem Biophys Res Commun. 1984;120:885–90.
Grundke-Iqbal I, Iqbal K, Tung YC, Quinlan M, Wisniewski HM, Binder LI. Abnormal phosphorylation of the microtubule-associated protein tau (tau) in Alzheimer cytoskeletal pathology. Proc Natl Acad Sci U S A. 1986;83:4913–7.
Hardy J, Selkoe DJ. The amyloid hypothesis of Alzheimer’s disease: progress and problems on the road to therapeutics. Science. 2002;297:353–6.
Giacobini E, Gold G. Alzheimer disease therapy—moving from amyloid-β to tau. Nat Rev Neurol. 2013;9:677–86.
Reitz C. Alzheimer’s disease and the amyloid cascade hypothesis: a critical review. Int J Alzheimers Dis. 2012;2012:369808.
Doody RS, Thomas RG, Farlow M, Iwatsubo T, Vellas B, Joffe S, et al. Phase 3 trials of solanezumab for mild-to-moderate Alzheimer’s disease. N Engl J Med. 2014;370:311–21.
Salloway S, Sperling R, Fox NC, Blennow K, Klunk W, Raskind M, et al. Two phase 3 trials of bapineuzumab in mild-to-moderate Alzheimer’s disease. N Engl J Med. 2014;370:322–33.
Vandenberghe R, Rinne JO, Boada M, Katayama S, Scheltens P, Vellas B, et al. Bapineuzumab for mild to moderate Alzheimer’s disease in two global, randomized, phase 3 trials. Alzheimers Res Ther. 2016;8(1):18.
Pasquier F, Sadowsky C, Holstein A, Leterme Gle P, Peng Y, Jackson N, et al. Two phase 2 multiple ascending-dose studies of vanutide cridificar (ACC-001) and QS-21 adjuvant in mild-to-moderate Alzheimer’s disease. J Alzheimers Dis. 2016;51:1131–43.
Alafuzoff I, Iqbal K, Friden H, Adolfsson R, Winblad B. Histopathological criteria for progressive dementia disorders: clinical-pathological correlation and classification by multivariate data analysis. Acta Neuropathol. 1987;74:209–25.
Arriagada PV, Growdon JH, Hedley-Whyte ET, Hyman BT. Neurofibrillary tangles but not senile plaques parallel duration and severity of Alzheimer’s disease. Neurology. 1992;42:631–9.
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;30:572–80.
Giannakopoulos P, Herrmann FR, Bussière T, Bouras C, Kövari E, Perl DP, et al. Tangle and neuron numbers, but not amyloid load, predict cognitive status in Alzheimer’s disease. Neurology. 2003;60:1495–500.
Sigurdsson EM. Tau immunotherapy. Neurodegener Dis. 2016;16:34–8.
Asuni AA, Boutajangout A, Quartermain D, Sigurdsson EM. Immunotherapy targeting pathological tau conformers in a tangle mouse model reduces brain pathology with associated functional improvements. J Neurosci. 2007;27:9115–29.
Bi M, Ittner A, Ke YD, Gotz J, Ittner LM. Tau-targeted immunization impedes progression of neurofibrillary histopathology in aged P301L tau transgenic mice. PLoS One. 2011;6:e26860.
Boimel M, Grigoriadis N, Lourbopoulos A, Haber E, Abramsky O, Rosenmann H. Efficacy and safety of immunization with phosphorylated tau against neurofibrillary tangles in mice. Exp Neurol. 2010;224:472–85.
Boutajangout A, Ingadottir J, Davies P, Sigurdsson EM. Passive immunization targeting pathological phospho-tau protein in a mouse model reduces functional decline and clears tau aggregates from the brain. J Neurochem. 2011;118:658–67.
Gu J, Congdon EE, Sigurdsson EM. Two novel Tau antibodies targeting the 396/404 region are primarily taken up by neurons and reduce Tau protein pathology. J Biol Chem. 2013;288:33081–95.
Troquier L, Caillierez R, Burnouf S, Fernandez-Gomez FJ, Grosjean ME, Zommer N, et al. Targeting phospho-Ser422 by active tau immunotherapy in the THYTau22 mouse model: a suitable therapeutic approach. Curr Alzheimer Res. 2012;9:397–405.
Theunis C, Crespo-Biel N, Gafner V, Pihlgren M, Lopez-Deber MP, Reis P, et al. Efficacy and safety of a liposome-based vaccine against protein Tau, assessed in tau.P301L mice that model tauopathy. PLoS One. 2013;8:e72301.
Yanamandra K, Kfoury N, Jiang H, Mahan TE, Ma S, Maloney SE, et al. Anti-tau antibodies that block tau aggregate seeding in vitro markedly decrease pathology and improve cognition in vivo. Neuron. 2013;80:402–14.
Chai X, Wu S, Murray TK, Kinley R, Cella CV, Sims H, et al. Passive immunization with anti-Tau antibodies in two transgenic models: reduction of Tau pathology and delay of disease progression. J Biol Chem. 2011;286:34457–67.
Collin L, Bohrmann B, Gopfert U, Oroszlan-Szovik K, Ozmen L, Gruninger F. Neuronal uptake of tau/pS422 antibody and reduced progression of tau pathology in a mouse model of Alzheimer’s disease. Brain. 2014;137:2834–46.
Sankaranarayanan S, Barten DM, Vana L, Devidze N, Yang L, Cadelina G, et al. Passive immunization with phospho-tau antibodies reduces tau pathology and functional deficits in two distinct mouse tauopathy models. PLoS One. 2015;10:e0125614.
Umeda T, Eguchi H, Kunori Y, Matsumoto Y, Taniguchi T, Mori H, et al. Passive immunotherapy of tauopathy targeting pSer413-tau: a pilot study in mice. Ann Clin Transl Neurol. 2015;2:241–55.
Dai CL, Chen X, Kazim SF, Liu F, Gong CX, Iqbal K. Passive immunization targeting the N-terminal projection domain of tau decreases tau pathology and improves cognition in a transgenic mouse model of Alzheimer disease and tauopathies. J Neural Transm (Vienna). 2015;122:607–17.
Anand K, Sabbagh M. Early investigational drugs targeting tau protein for the treatment of Alzheimer’s disease. Expert Opin Investig Drugs. 2015;24:1355–60.
Iqbal K, Grundke-Iqbal I, Zaidi T, Merz PA, Wen GY, Shaikh SS, et al. Defective brain microtubule assembly in Alzheimer’s disease. Lancet. 1986;2:421–6.
Alonso AC, Zaidi T, Grundke-Iqbal I, Iqbal K. Role of abnormally phosphorylated tau in the breakdown of microtubules in Alzheimer disease. Proc Natl Acad Sci U S A. 1994;91:5562–6.
Alonso AC, Grundke-Iqbal I, Iqbal K. Alzheimer’s disease hyperphosphorylated tau sequesters normal tau into tangles of filaments and disassembles microtubules. Nat Med. 1996;2:783–7.
Clavaguera F, Bolmont T, Crowther RA, Abramowski D, Frank S, Probst A, et al. Transmission and spreading of tauopathy in transgenic mouse brain. Nat Cell Biol. 2009;11:909–13.
Clavaguera F, Akatsu H, Fraser G, Crowther RA, Frank S, Hench J, et al. Brain homogenates from human tauopathies induce tau inclusions in mouse brain. Proc Natl Acad Sci U S A. 2013;110:9535–40.
Sanders DW, Kaufman SK, DeVos SL, Sharma AM, Mirbaha H, Li A, et al. Distinct tau prion strains propagate in cells and mice and define different tauopathies. Neuron. 2014;82:1271–88.
Hu W, Zhang X, Tung YC, Liu F, Iqbal K. Hyperphosphorylation determines both the spread and the morphology of tau pathology. Alzheimers Dement. 2016;12:1066–77.
Mohamed NV, Herrou T, Plouffe V, Piperno N, Leclerc N. Spreading of tau pathology in Alzheimer’s disease by cell-to-cell transmission. Eur J Neurosci. 2013;37:1939–48.
Avila J, Simon D, Diaz-Hernandez M, Pintor J, Hernandez F. Sources of extracellular tau and its signaling. J Alzheimers Dis. 2014;40 Suppl 1:S7–S15.
Flight MH. Neurodegenerative disease: tau immunotherapy targets transcellular propagation. Nat Rev Drug Discov. 2013;12:904.
Frost B, Jacks RL, Diamond MI. Propagation of tau misfolding from the outside to the inside of a cell. J Biol Chem. 2009;284:12845–52.
Zilka N, Kontsekova E, Novak M. Chaperone-like antibodies targeting misfolded tau protein: new vistas in the immunotherapy of neurodegenerative foldopathies. J Alzheimers Dis. 2008;15:169–79.
Oddo S, Caccamo A, Shepherd JD, Murphy MP, Golde TE, Kayed R, et al. Triple-transgenic model of Alzheimer’s disease with plaques and tangles: intracellular Aβ and synaptic dysfunction. Neuron. 2003;39:409–21.
Blanchard J, Wanka L, Tung YC, Del Carmen Cárdenas-Aguayo M, LaFerla FM, Iqbal K, et al. Pharmacologic reversal of neurogenic and neuroplastic abnormalities and cognitive impairments without affecting Aβ and tau pathologies in 3×Tg-AD mice. Acta Neuropathol. 2010;120:605–21.
Kazim SF, Blanchard J, Dai CL, Tung YC, LaFerla FM, Iqbal K, et al. Disease modifying effect of chronic oral treatment with a neurotrophic peptidergic compound in a triple transgenic mouse model of Alzheimer’s disease. Neurobiol Dis. 2014;71:110–30.
Kascsak RJ, Rubenstein R, Merz PA, Tonna-DeMasi M, Fersko R, Carp RI, et al. Mouse polyclonal and monoclonal antibody to scrapie-associated fibril proteins. J Virol. 1987;61:3688–93.
Morris RG, Garrud P, Rawlins JN, O’Keefe J. Place navigation impaired in rats with hippocampal lesions. Nature. 1982;297:681–3.
D’Hooge R, De Deyn PP. Applications of the Morris water maze in the study of learning and memory. Brain Res Brain Res Rev. 2001;36:60–90.
Vorhees CV, Williams MT. Morris water maze: procedures for assessing spatial and related forms of learning and memory. Nat Protoc. 2006;1:848–58.
Bevins RA, Besheer J. Object recognition in rats and mice: a one-trial non-matching-to-sample learning task to study ‘recognition memory’. Nat Protoc. 2006;1:1306–11.
Antunes M, Biala G. The novel object recognition memory: neurobiology, test procedure, and its modifications. Cogn Process. 2012;13:93–110.
Contestabile A, Greco B, Ghezzi D, Tucci V, Benfenati F, Gasparini L. Lithium rescues synaptic plasticity and memory in Down syndrome mice. J Clin Invest. 2013;123:348–61.
Assini FL, Duzzioni M, Takahashi RN. Object location memory in mice: pharmacological validation and further evidence of hippocampal CA1 participation. Behav Brain Res. 2009;204:206–11.
Murai T, Okuda S, Tanaka T, Ohta H. Characteristics of object location memory in mice: behavioral and pharmacological studies. Physiol Behav. 2007;90:116–24.
Congdon EE, Gu J, Sait HB, Sigurdsson EM. Antibody uptake into neurons occurs primarily via clathrin-dependent Fcγ receptor endocytosis and is a prerequisite for acute tau protein clearance. J Biol Chem. 2013;288:35452–65.
Krishnamurthy PK, Deng Y, Sigurdsson EM. Mechanistic studies of antibody-mediated clearance of tau aggregates using an ex vivo brain slice model. Front Psychiatry. 2011;2:59.
Watkinson RE, McEwan WA, James LC. Intracellular antibody immunity. J Clin Immunol. 2014;34 Suppl 1:S30–4.
Shamir DB, Rosenqvist N, Rasool S, Pedersen JT, Sigurdsson EM. Internalization of tau antibody and pathological tau protein detected with a flow cytometry multiplexing approach. Alzheimers Dement. 2016;12:1098–107.
Pedersen JT, Sigurdsson EM. Tau immunotherapy for Alzheimer’s disease. Trends Mol Med. 2015;21:394–402.
Chai X, Dage JL, Citron M. Constitutive secretion of tau protein by an unconventional mechanism. Neurobiol Dis. 2012;48:356–66.
Shah KH, Zhang B, Ramachandran V, Herman PK. Processing body and stress granule assembly occur by independent and differentially regulated pathways in Saccharomyces cerevisiae. Genetics. 2013;193:109–23.
Jack Jr CR, Knopman DS, Jagust WJ, Petersen RC, Weiner MW, Aisen PS, et al. Tracking pathophysiological processes in Alzheimer’s disease: an updated hypothetical model of dynamic biomarkers. Lancet Neurol. 2013;12:207–16.
Maia LF, Kaeser SA, Reichwald J, Hruscha M, Martus P, Staufenbiel M, et al. Changes in amyloid-β and tau in the cerebrospinal fluid of transgenic mice overexpressing amyloid precursor protein. Sci Transl Med. 2013;5:194re192.
Bright J, Hussain S, Dang V, Wright S, Cooper B, Byun T, et al. Human secreted tau increases amyloid-β production. Neurobiol Aging. 2015;36:693–709.
Meredith Jr JE, Sankaranarayanan S, Guss V, Lanzetti AJ, Berisha F, Neely RJ, et al. Characterization of novel CSF tau and ptau biomarkers for Alzheimer’s disease. PLoS One. 2013;8:e76523.
Pooler AM, Phillips EC, Lau DH, Noble W, Hanger DP. Physiological release of endogenous tau is stimulated by neuronal activity. EMBO Rep. 2013;14:389–94.
Braak H, Braak E. Frequency of stages of Alzheimer-related lesions in different age categories. Neurobiol Aging. 1997;18:351–7.
Braak H, Zetterberg H, Del Tredici K, Blennow K. Intraneuronal tau aggregation precedes diffuse plaque deposition, but amyloid-β changes occur before increases of tau in cerebrospinal fluid. Acta Neuropathol. 2013;126:631–41.
Shen Y, Yang L, Li R. What does complement do in Alzheimer’s disease? Old molecules with new insights. Transl Neurodegener. 2013;2:21.
Yasojima K, Schwab C, McGeer EG, McGeer PL. Up-regulated production and activation of the complement system in Alzheimer’s disease brain. Am J Pathol. 1999;154:927–36.
Bonifati DM, Kishore U. Role of complement in neurodegeneration and neuroinflammation. Mol Immunol. 2007;44:999–1010.
Wyss-Coray T, Yan F, Lin AH, Lambris JD, Alexander JJ, Quigg RJ, et al. Prominent neurodegeneration and increased plaque formation in complement-inhibited Alzheimer’s mice. Proc Natl Acad Sci U S A. 2002;99:10837–42.
Maier M, Peng Y, Jiang L, Seabrook TJ, Carroll MC, Lemere CA. Complement C3 deficiency leads to accelerated amyloid β plaque deposition and neurodegeneration and modulation of the microglia/macrophage phenotype in amyloid precursor protein transgenic mice. J Neurosci. 2008;28:6333–41.
Fu H, Liu B, Frost JL, Hong S, Jin M, Ostaszewski B, et al. Complement component C3 and complement receptor type 3 contribute to the phagocytosis and clearance of fibrillar Aβ by microglia. Glia. 2012;60:993–1003.
Choucair-Jaafar N, Laporte V, Levy R, Poindron P, Lombard Y, Gies JP. Complement receptor 3 (CD11b/CD18) is implicated in the elimination of β-amyloid peptides. Fundam Clin Pharmacol. 2011;25:115–22.
Fonseca MI, Chu SH, Berci AM, Benoit ME, Peters DG, Kimura Y, et al. Contribution of complement activation pathways to neuropathology differs among mouse models of Alzheimer’s disease. J Neuroinflammation. 2011;8:4.
d’Abramo C, Acker CM, Jimenez HT, Davies P. Tau passive immunotherapy in mutant P301L mice: c.
Tatebayashi Y, Iqbal K, Grundke-Iqbal I. Dynamic regulation of expression and phosphorylation of tau by fibroblast growth factor-2 in neural progenitor cells from adult rat hippocampus. J Neurosci. 1999;19:5245–54.