Various Aβ assemblies are involved in mediating reduced synaptic connections, impaired memory and other cognitive impairments in AD (Huang and Mucke, 2012).
Aβ bind to α7 nAChRs and form complexes in the AD brain (Wang et al., 2000; Lilja et al., 2011), may contribute to the disruption of synaptic function (Snyder et al., 2005).
We characterized the interaction between different nAChR subtypes and fibrillar Aβ using binding assays in postmortem brain from AD and controls using drugs with different mechanisms of action, including selective nAChR subtype agonists, and PIB to detect fibrillar Aβ. The increase in 3H-PIB binding induced by full α7 nAChR and partial α4β2 nAChR agonist varenicline and partial α7 nAChR agonist JN403 was blocked by α7 nAChR antagonists, methyllycaconitine, α-bungarotoxin and mecamylamine, but not by the α4β2 antagonist dihydro-β-erythroidine (Figure 9).
Figure 9 Effects of 1 µM JN403, 1 µM varenicline (A, C), 100 nM and 1 µM galantamine, and 50 nM dimebon (B, D) in combination of 1 µM MLA or 1 µM Mec, 1 µM DHβE, 100 nM α-BgTX on 3H-PIB binding in the frontal cortical homogenates from AD patients (n = 5) and controls (n = 5). *p <0.05, **p <0.01 ***p <0.001 compared to untreated; †p <0.05, ††p <0.01 compared to JN403/varenicline/galantamine/dimebon. α-BgTX = α-bungarotoxin; dihydro-β-erythroidine = DHβE; MLA= methyllycaconitine; Mec = mecamylamine; Results are given as means ± S.E.M (Ni et al., 2013a).
3H-PIB binding levels were mostly in the P1 fraction, but detectable in the P2
membrane fraction. JN403-induced increase in 3H-PIB binding was from P1 fraction, suggesting that this Aβ−α7 nAChR interaction occurs on the extracellular side (Figure 10). Neither AChEI galantamine nor NMDAR antagonist memantine altered 3H-PIB binding levels in the AD brain. It is suggested that the binding site of α7 nAChR drugs might partly overlap the fibrillar Aβ binding site to α7 nAChR. Recent evidence suggested that a specific aromatic residue within the agonist binding domain of α7 nAChR was involved in this interaction (Khan et al., 2010; Tong et al., 2011). The α7 nAChRs agonists may therefore induce the release of Aβ from preformed complexes, thus representing a potential therapeutic target in AD (Paper V).
However, functional studies on Aβ-α7 nAChRs interaction is not fully clear: both activation (Dineley et al., 2002; Dougherty et al., 2003), inhibition (Liu et al., 2001;
Pettit et al., 2001) or both (Lilja et al., 2011) has been reported, .Other study suggested an involvement of lipid rafts in this Aβ-α7 nAChR interaction (Small et al., 2007).
.
Figure 10 A) Specific 3H-PIB binding (% crude homogenate) on frontal cortical crude homogenates, P2 (membrane) fraction, S2 fraction from AD patients (n = 5). B) Effects of 1 µM JN403 on 3H-PIB binding in the frontal cortical crude homogenates and P2 fraction of AD brain (n = 5). **p <0.01; Results are given as means ± S.E.M. (Ni et al., 2013a).
Paper V Limitations: we were not able to differentiate between Aβ40 and Aβ42, since the amyloid ligand PIB binds to both peptideswith similar affinity. It has been shown that Aβ could bind to phospholipid membranes with a relatively high affinity
(McLaurin and Chakrabartty, 1996). Several other possible membrane receptors to which Aβ binds have been reported, including the α7 nAChR, the NMDAR, and the neurotrophin receptor p75.
5 CONCLUDING REMARKS
Key findings in the thesis:
• Amyloid PET tracers PIB, florbetaben, florbetapir, AZD2184, and BTA-1 detected a similar high-affinity binding site and a varying low-affinity binding site in postmortem sporadic AD brain. BF-227 showed a distinct proportion of binding to the two sites, and FDNNP detected partially the low-affinity site.
AZD2184 detected an additional site in ADAD frontal cortex (summarized in Figure 11). Striatal 3H-PIB binding was higher in ADAD than in sporadic AD brains. Amyloid tracer binding to fibrillar Aβ was influenced by resveratrol and AZD2184 showed the greatest changes. These findings suggest a multiple binding site model for amyloid tracers in the AD brain.
• Astrocytosis measured by 11C-DED appeared prior to the increase in amyloid accumulation measured by 11C-AZD2184 in the transgenic AD mouse model, suggesting that astrocytosis is an early event in human AD.
• α7 nAChR agonists could induce the release of Aβ from preformed Aβ-α7 nAChR complexes (Figure 12) and thus could represent a potential
therapeutic target for AD.
Figure 11 Proposed multiple binding sites for amyloid tracers on Aβ fibrils in the brain. PIB, BTA-1, AZD2184, florbetaben and florbetapir (red) bind 90 % to the high-affinity binding site 1 (affinity 10-10-3x10-9M) and to the low-affinity binding site 2 (affinity varying between 10-9 -10-8M); BF-227 (blue) bind to the binding site 1 with 20 % and to the low affinity binding site 3 with 60 % (affinity 10-7M above); FDDNP (yellow) bind 40 % to the binding site 2. In frontal cortex from ADAD patients, AZD2184 detects an additional binding site 1b (green) (affinity 10-9 M-10-8 M) in addition to the binding site 1, 3.
Figure 12 An illustration of the proposed interactions between different forms of Aβ and α7 nAChRs (A) and of α7 nAChR agonists interrupting this interaction (B) (Ni et al., 2013a). Aβ assemblies of varying composition may interact differently with α7 nAChRs (Lee and Wang, 2003; Bokvist et al., 2004; Lilja et al., 2011).
Amyloid tracers that detect small forms of Aβ, such as protofibrils, and oligomeric Aβ will provide valuable insight. One of the strategies currently under investigation is to target these smaller forms of Aβ use Aβ protofibril-binding antibody (Magnusson et al., 2013; Viola et al., 2015). The causes and time courses of the different
pathophysiological processes in AD remain unclear. Knowledge of Aβ binding sites, interaction with inflammation, and synaptic mechanisms in AD will facilitate the development of new diagnostic imaging tracers and drug targets for the AD.
6 ACKNOWLEDGEMENTS
I would like to thank all the people who have helped me during these years in Prof.
Agneta Nordberg's lab at Div. of Translational Alzheimer Neurobiology, Center for Alzheimer Research, Dept. of Neurobiology, Care Sciences and Society at Karolinska Institutet.
My main supervisor:
Prof. Agneta Nordberg: I would like to express my immense gratitude to you for giving me the opportunity to work on this fantastic research project with you and to learn from you for 5 years. You opened a window for my scientific life. Thank you for sharing your passion for and insights into Alzheimer Research and scientific thinking.
Thank you for taking time from your super busy schedule to give me invaluable guidance on my projects, manuscripts, and presentations. Thank you for your patience with me and my mistakes. I feel really lucky to have worked on these interesting projects and to have been able to publish the findings. This thesis would not have happened without you.
My co-supervisors:
I am deeply grateful to Prof. Per-Göran Gillberg, for inspiring telephone conferences every Friday and for taking the time to visit Huddinge all the way from Gothenberg or from far away around the world (e.g. the U.S. and India). Thank you for your
enthusiasm about the data, for our discussions, and for analyzing all the experimental problems I had. Thank you for sharing your advice about my future career.
I want to especially thank Dr. Amelia Marutle for your guidance with project planning, manuscript writing, and all the detailed trouble shooting. Thank you for teaching and guiding me in how to think scientifically/logically and all the
experimental work over these years. Thank you for taking long hours and explaining in detail for me whenever I felt confused. You were really instrumental in my studies and my life here.
Coauthors and collaborators:
I would like to thank all my coauthors in the papers and manuscripts. I especially wish to thank Prof. Bengt Långström for your insights into amyloid tracers, Dr.
Elena Rodriguez-Vieitez for all your efforts in microPET modeling and for the manuscript writing we did together, and Dr. Larysa Voytenko for your amazing immunostaining pictures. I would also like to thank Dr. Micheal Schöll and Dr.
Anders Wall for your help when I first started in the group, Prof. Ove Almkvist for explaining psychological tests, Prof. IL Han Choo for lectures on statistical modeling, Prof. Matti Viitanen, Dr. Liisa Myllykangas, Prof. Hannu Kalimo,Prof.Inger Nennesmo, and Prof. Nenad Bogdanovic for neuropathological staining and discussions, Prof. Balázs Gulyás, Prof. Christer Halldin, Miklós Tóth, and Jenny Häggkvist for microPET scans. Thank you Jennie Röjdner, Assar Bergfors, and Carina Thome for making the lab a nicer place to be. Dr. N. Arul Murugan for help with the amyloid structure. I really enjoyed the opportunity to work with you and the discussions we had.
Colleagues at the Division of Translational Alzheimer Neurobiology:
I want to thank Taher Darreh-Shori, Christina Unger, Laëtitia Lemoine, Tamanna Mustafiz, Swetha Vijayaraghavan, Azadeh Karami, Ahmadul Kadir, Konstantinos Chiotis, Erica Lana, Anna Lilja, Linn Wicklund, Stephen Carter, Karim Farid, Karin Forsström, Erik Thalme, Fuxiang Bao, Rajnish Kumar, Fredrik Engman, Laure Saint-Aubert, Emmy Rannikko, Antoine Leuzy, Nahrain Oshalim, Sabrina Jung, Karen Butina, Stephanie Shaia, Anna Sanderberg, Isabell Wärmé, Daiane Priscila Simao-Silva, Shiva Nowzari, and Malahat Mousavi for help with the lab, advices, discussions and for the laughter in the office. I'd also like to thank our administrator Agneta Lindahl for help with the documents and for the Swedish mushroom picking and forest trips, and Antona Wagstaff for help with language and editing.
I want to thank all my many dear colleagues and friends at the NVS department, especially Prof. Bengt Winblad, Gunilla Johansson of Swedish Brain Power and great workshop every year. Prof. Åker Seiger for the enlightening Kandel book seminar during the doctoral study. Prof. Jie Zhu and Prof. Jingjin Pei for invaluable advice and taking care of all the Chinese students. Thanks to Homira Behbahani and Taher Darreh-Shori for the inspiring PhD seminar. Thanks to Prof. Caroline Graff and Annica Rönnbäck for helps with the tissue from brain bank at KI. Thanks to Prof. Marianne Schultzberg, Maria Eriksdotter, Erik Sundström, Maria Ankarcrona for your support for doctoral student education.
Thank you to Alina Codita, Deniela Enache, Heela Sarlus, Linda
Rettenwander, Eric Westman, Erika Bereczki, Ronnie Folksesson, Pavla Cermakova, Carlos Aguilar, Daniel Padilla Ferreira, Erik Hjorth, Olga Voevodskaya, Kevin Grimes, Joanna Braga Pereire, Muhammad Al Mustafa Ismail, Annelie Pamren, Walid Tajeddinn, Torbjörn Persson, Annette
Kalsson, Alexandra Lebedova, Veronica Cortes-Toro for your great support.
Thank you my dear Chinese colleagues Xiaozheng Li, Zhi Tang, Mingqing Zhu, Qiupin Jia, Ning Xu, Hongliang Zhang, Xiangyu Zhen, Yang Ruan, Chi Ma, Xu Wang, Dan Wang, Rui Wang, Bo Zhang, Gefei Chen, Xiuzhe Wang, Shanzheng Yang, Siqing Wu Zhongshi Xie and Xingmei Zhang for family feeling.
Thank you to my friends in Stockholm: Jingwen Wang, Yan Wang, Yan-Bee Ng and Weng-Onn Liu, Yao Pei, Liwen Wu, Wenjie Shen, Hongqian Yang, Qu Ying, Sarah Mak, Jingtian Chen, Han Zhang, Jia Sun, Sunny Tsoi Yat Long, Swapnali Barde, Subu Surendran Rajasekaran, Michael Rönnerblad, Simona Conte, Simei Yu, Tunhe Zhou, Yan Li, Jian Yan and Jingwei Zhou for your sharing and encouragement. Thank you to my friends in Uppsala:
Lingyun Xiao, Mingyu Wu, Wangshu Jiang, Xiaohu Guo, and Lei Zhang and in Shanghai: Lei Cao and Xiaolin Xia.
I would also like to thank the foundations and grant-givers for making the project and thesis possible: Swedish Brain Power, EU FP7 large scale integrating project INMiND, the Foundation for Old Servants, Demensfonden, Gun and Bertil Stohne's Foundation, Sigurd and Elsa Golje's Foundation and Ragnhild and Einar Lundström's Memorial Foundation.
However, my greatest thanks go to my father and mother for your support; I'm sorry to have been so far away for so many years.
7 REFERENCES
Agdeppa ED, Kepe V, Liu J, Flores-Torres S, Satyamurthy N, Petric A, Cole GM, Small GW, Huang SC, Barrio JR (2001) Binding characteristics of radiofluorinated
6-dialkylamino-2-naphthylethylidene derivatives as positron emission tomography imaging probes for beta-amyloid plaques in Alzheimer's disease. J Neurosci 21:RC189.
Akiyama H et al. (2000) Inflammation and Alzheimer’s disease. Neurobiol Aging 21:383-421.
Albert MS, DeKosky ST, Dickson D, Dubois B, Feldman HH, Fox NC, Gamst A, Holtzman DM, Jagust WJ, Petersen RC, Snyder PJ, Carrillo MC, Thies B, Phelps CH (2011) The diagnosis of mild cognitive impairment due to Alzheimer’s disease: Recommendations from the National Institute on Aging-Alzheimer’s Association workgroups on
diagnostic guidelines for Alzheimer's disease. Alzheimer's and Dementia 7:270-279.
Ashe KH, Zahs KR (2010) Probing the Biology of Alzheimer's Disease in Mice. Neuron 66:631-645.
Ballard C, Gauthier S, Corbett A, Brayne C, Aarsland D, Jones E (2011) Alzheimer's disease.
LANCET 377:1019-1031.
Barthel H, Gertz HJ, Dresel S, Peters O, Bartenstein P, Buerger K, Hiemeyer F, Wittemer-Rump SM, Seibyl J, Reininger C, Sabri O (2011) Cerebral amyloid-beta PET with florbetaben (18F) in patients with Alzheimer's disease and healthy controls: a multicentre phase 2 diagnostic study. Lancet Neurol 10:424-435.
Basun H, Bogdanovic N, Ingelsson M, Almkvist O, Naslund J, Axelman K, Bird TD, Nochlin D, Schellenberg GD, Wahlund LO, Lannfelt L (2008) Clinical and neuropathological features of the arctic APP gene mutation causing early-onset Alzheimer disease. Arch Neurol 65:499-505.
Bateman RJ et al. (2012) Clinical and biomarker changes in dominantly inherited Alzheimer's disease. N Engl J Med 367:795-804.
Benilova I, Karran E, De Strooper B (2012) The toxic Abeta oligomer and Alzheimer's disease:
an emperor in need of clothes. Nat Neurosci 15:349-357.
Benzinger TL et al. (2013) Regional variability of imaging biomarkers in autosomal dominant Alzheimer's disease. Proc Natl Acad Sci U S A 110:E4502-4509.
Bertram L, Lill CM, Tanzi RE (2010) The genetics of Alzheimer disease: back to the future.
Neuron 68:270-281.
Bettens K, Sleegers K, Van Broeckhoven C (2013) Genetic insights in Alzheimer's disease.
Lancet Neurol 12:92-104.
Bogdanovic N, Corder E, Lannfelt L, Winblad B (2002) APOE polymorphism and clinical duration determine regional neuropathology in Swedish APP(670, 671) mutation carriers: implications for late-onset Alzheimer's disease. J Cell Mol Med 6:199-214.
Bokvist M, Lindstrom F, Watts A, Grobner G (2004) Two types of Alzheimer's beta-amyloid (1-40) peptide membrane interactions: aggregation preventing transmembrane anchoring versus accelerated surface fibril formation. J Mol Biol 335:1039-1049.
Braak H, Braak E (1990) Alzheimer's disease: striatal amyloid deposits and neurofibrillary changes. J Neuropathol Exp Neurol 49:215-224.
Braak H, Braak E (1991) Neuropathological stageing of Alzheimer-related changes. Acta Neuropathol 82:239-259.
Braak H, Braak E (1997) Frequency of stages of Alzheimer-related lesions in different age categories. Neurobiol Aging 18:351-357.
Breitner JC, Baker LD, Montine TJ, Meinert CL, Lyketsos CG, Ashe KH, Brandt J, Craft S, Evans DE, Green RC, Ismail MS, Martin BK, Mullan MJ, Sabbagh M, Tariot PN
(2011) Extended results of the Alzheimer's disease anti-inflammatory prevention trial.
Alzheimers Dement 7:402-411.
Brendel M, Delker A, Rotzer C, Boning G, Carlsen J, Cyran C, Mille E, Gildehaus FJ, Cumming P, Baumann K, Steiner H, Haass C, Herms J, Bartenstein P, Rominger A (2014) Impact of partial volume effect correction on cerebral beta-amyloid imaging in APP-Swe mice using [(18)F]-florbetaben PET. NeuroImage 84:843-853.
Brettschneider J, Tredici KD, Lee VMY, Trojanowski JQ (2015) Spreading of pathology in neurodegenerative diseases: a focus on human studies. Nat Rev Neurosci advance online publication.
Buckingham SD, Jones AK, Brown LA, Sattelle DB (2009) Nicotinic acetylcholine receptor signalling: roles in Alzheimer's disease and amyloid neuroprotection. Pharmacol Rev 61:39-61.
Buckner RL, Sepulcre J, Talukdar T, Krienen FM, Liu H, Hedden T, Andrews-Hanna JR, Sperling RA, Johnson KA (2009) Cortical Hubs Revealed by Intrinsic Functional Connectivity: Mapping, Assessment of Stability, and Relation to Alzheimer's Disease.
Journal of Neuroscience 29:1860-1873.
Cagnin A, Brooks D, Kennedy A, Gunn R, Myers R, Turkheimer F, Jones T, Banati R (2001) In-vivo measurement of activated microglia in dementia. The Lancet 358:461-467.
Caroli A, Prestia A, Galluzzi S, Ferrari C, van der Flier WM, Ossenkoppele R, Van Berckel B, Barkhof F, Teunissen C, Wall AE, Carter SF, Scholl M, Choo IH, Grimmer T, Redolfi A, Nordberg A, Scheltens P, Drzezga A, Frisoni GB (2015) Mild cognitive impairment with suspected nonamyloid pathology (SNAP): Prediction of progression. Neurology 84:508-515.
Carter SF, Scholl M, Almkvist O, Wall A, Engler H, Langstrom B, Nordberg A (2012)
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 53:37-46.
Chakrabarty P, Li A, Ceballos-Diaz C, Eddy JA, Funk CC, Moore B, DiNunno N, Rosario AM, Cruz PE, Verbeeck C, Sacino A, Nix S, Janus C, Price ND, Das P, Golde TE (2015) IL-10 Alters Immunoproteostasis in APP Mice, Increasing Plaque Burden and Worsening Cognitive Behavior. Neuron 85:519-533.
Chebaro Y, Jiang P, Zang T, Mu Y, Nguyen PH, Mousseau N, Derreumaux P (2012) Structures of Abeta17-42 trimers in isolation and with five small-molecule drugs using a
hierarchical computational procedure. J Phys Chem B 116:8412-8422.
Chetelat G (2013) Alzheimer disease: Abeta-independent processes-rethinking preclinical AD.
Nat Rev Neurol 9:123-124.
Chetelat G, Desgranges B, de la Sayette V, Viader F, Eustache F, Baron JC (2003) Mild cognitive impairment: Can FDG-PET predict who is to rapidly convert to Alzheimer's disease? Neurology 60:1374-1377.
Chien DT, Szardenings AK, Bahri S, Walsh JC, Mu F, Xia C, Shankle WR, Lerner AJ, Su MY, Elizarov A, Kolb HC (2014) Early clinical PET imaging results with the novel PHF-tau radioligand [F18]-T808. J Alzheimers Dis 38:171-184.
Choo IH, Ni R, Schöll M, Wall A, Almkvist O, Nordberg A (2013) Combination of 18F-FDG PET and cerebrospinal fluid biomarkers as a better predictor of the progression to Alzheimer's disease in mild cognitive impairment patients. J Alzheimers Dis 33:929-939.
Choo IL, Carter SF, Schöll ML, Nordberg A (2014) Astrocytosis measured by (1)(1)C-deprenyl PET correlates with decrease in gray matter density in the parahippocampus of
prodromal Alzheimer's patients. Eur J Nucl Med Mol Imaging 41:2120-2126.
Cirrito JR, Yamada KA, Finn MB, Sloviter RS, Bales KR, May PC, Schoepp DD, Paul SM, Mennerick S, Holtzman DM (2005) Synaptic activity regulates interstitial fluid amyloid-beta levels in vivo. Neuron 48:913-922.
Clark CM, Pontecorvo MJ, Beach TG, Bedell BJ, Coleman RE, Doraiswamy PM, Fleisher AS, Reiman EM, Sabbagh MN, Sadowsky CH, Schneider JA, Arora A, Carpenter AP, Flitter ML, Joshi AD, Krautkramer MJ, Lu M, Mintun MA, Skovronsky DM (2012) Cerebral PET with florbetapir compared with neuropathology at autopsy for detection of neuritic amyloid-beta plaques: a prospective cohort study. Lancet Neurol 11:669-678.
Clark CM, Schneider JA, Bedell BJ, Beach TG, Bilker WB, Mintun MA, Pontecorvo MJ, Hefti F, Carpenter AP, Flitter ML, Krautkramer MJ, Kung HF, Coleman RE, Doraiswamy PM, Fleisher AS, Sabbagh MN, Sadowsky CH, Reiman EP, Zehntner SP, Skovronsky DM (2011) Use of florbetapir-PET for imaging beta-amyloid pathology. JAMA 305:275-283.
Cole GB, Keum G, Liu J, Small GW, Satyamurthy N, Kepe V, Barrio JR (2010) Specific estrogen sulfotransferase (SULT1E1) substrates and molecular imaging probe candidates. Proc Natl Acad Sci U S A 107:6222-6227.
Cook D, Brown D, Alexander R, March R, Morgan P, Satterthwaite G, Pangalos MN (2014) Lessons learned from the fate of AstraZeneca's drug pipeline: a five-dimensional framework. Nat Rev Drug Discov 13:419-431.
Corbett A, Pickett J, Burns A, Corcoran J, Dunnett SB, Edison P, Hagan JJ, Holmes C, Jones E, Katona C, Kearns I, Kehoe P, Mudher A, Passmore A, Shepherd N, Walsh F, Ballard C (2012) Drug repositioning for Alzheimer's disease. Nat Rev Drug Discov 11:833-846.
Crary JF et al. (2014) Primary age-related tauopathy (PART): a common pathology associated with human aging. Acta Neuropathol 128:755-766.
Crook R, Verkkoniemi A, Perez-Tur J, Mehta N, Baker M, Houlden H, Farrer M, Hutton M, Lincoln S, Hardy J, Gwinn K, Somer M, Paetau A, Kalimo H, Ylikoski R, Poyhonen M, Kucera S, Haltia M (1998) A variant of Alzheimer's disease with spastic paraparesis and unusual plaques due to deletion of exon 9 of presenilin 1. Nat Med 4:452-455.
Cruchaga C et al. (2014) Rare coding variants in the phospholipase D3 gene confer risk for Alzheimer's disease. Nature 505:550-554.
Cselenyi Z, Jonhagen ME, Forsberg A, Halldin C, Julin P, Schou M, Johnstrom P, Varnas K, Svensson S, Farde L (2012) Clinical Validation of 18F-AZD4694, an Amyloid-beta-Specific PET Radioligand. J Nucl Med.
Curtis C et al. (2015) Phase 3 Trial of Flutemetamol Labeled With Radioactive Fluorine 18 Imaging and Neuritic Plaque Density. JAMA Neurol.
Dineley KT, Pandya AA, Yakel JL (2015) Nicotinic ACh receptors as therapeutic targets in CNS disorders. Trends Pharm Sci.
Dineley KT, Bell KA, Bui D, Sweatt JD (2002) beta -Amyloid peptide activates alpha 7 nicotinic acetylcholine receptors expressed in Xenopus oocytes. J Biol Chem 277:25056-25061.
Donohue MC, Sperling RA, Salmon DP, Rentz DM, Raman R, Thomas RG, Weiner M, Aisen PS (2014) The preclinical Alzheimer cognitive composite: measuring amyloid-related decline. JAMA Neurol 71:961-970.
Doody RS, Thomas RG, Farlow M, Iwatsubo T, Vellas B, Joffe S, Kieburtz K, Raman R, Sun X, Aisen PS, Siemers E, Liu-Seifert H, Mohs R (2014) Phase 3 trials of solanezumab for mild-to-moderate Alzheimer's disease. N Engl J Med 370:311-321.
Dougherty JJ, Wu J, Nichols RA (2003) Beta-amyloid regulation of presynaptic nicotinic receptors in rat hippocampus and neocortex. J Neurosci 23:6740-6747.
Drzezga A, Lautenschlager N, Siebner H, Riemenschneider M, Willoch F, Minoshima S, Schwaiger M, Kurz A (2003) Cerebral metabolic changes accompanying conversion of mild cognitive impairment into Alzheimer's disease: a PET follow-up study. Eur J Nucl Med Mol Imaging 30:1104-1113.
Dubois A, Herard AS, Delatour B, Hantraye P, Bonvento G, Dhenain M, Delzescaux T (2010) Detection by voxel-wise statistical analysis of significant changes in regional cerebral glucose uptake in an APP/PS1 transgenic mouse model of Alzheimer's disease.
Neuroimage 51:586-598.
Dubois B, Feldman HH, Jacova C, Dekosky ST, Barberger-Gateau P, Cummings J, Delacourte A, Galasko D, Gauthier S, Jicha G, Meguro K, O'Brien J, Pasquier F, Robert P, Rossor M, Salloway S, Stern Y, Visser PJ, Scheltens P (2007) Research criteria for the diagnosis of Alzheimer's disease: revising the NINCDS-ADRDA criteria. Lancet Neurol 6:734-746.
Dubois B et al. (2014) Advancing research diagnostic criteria for Alzheimer's disease: the IWG-2 criteria. Lancet Neurol 13:614-629.
Duyckaerts C, Braak H, Brion JP, Buee L, Del Tredici K, Goedert M, Halliday G, Neumann M, Spillantini MG, Tolnay M, Uchihara T (2015) PART is part of Alzheimer disease. Acta Neuropathol.
Engler H, Forsberg A, Almkvist O, Blomquist G, Larsson E, Savitcheva I, Wall A, Ringheim A, Langstrom B, Nordberg A (2006) Two-year follow-up of amyloid deposition in patients with Alzheimer's disease. Brain 129:2856-2866.
Exalto LG, Quesenberry CP, Barnes D, Kivipelto M, Biessels GJ, Whitmer RA (2014) Midlife risk score for the prediction of dementia four decades later. Alzheimers Dement 10:562-570.
Fagan AM et al. (2014) Longitudinal change in CSF biomarkers in autosomal-dominant Alzheimer's disease. Sci Transl Med 6:226ra230.
Fleisher AS et al. (2015) Associations Between Biomarkers and Age in the Presenilin 1 E280A Autosomal Dominant Alzheimer Disease Kindred: A Cross-sectional Study. JAMA Neurol.
Forsberg A, Engler H, Almkvist O, Blomquist G, Hagman G, Wall A, Ringheim A, Langstrom B, Nordberg A (2008) PET imaging of amyloid deposition in patients with mild cognitive impairment. Neurobiol Aging 29:1456-1465.
Fowler JS, Logan J, Volkow ND, Wang G-J (2005) Translational Neuroimaging: Positron Emission Tomography Studies of Monoamine Oxidase. Molecular Imaging and Biology 7:377-387.
Friden M, Bergstrom F, Wan H, Rehngren M, Ahlin G, Hammarlund-Udenaes M, Bredberg U (2011) Measurement of unbound drug exposure in brain: modeling of pH partitioning explains diverging results between the brain slice and brain homogenate methods. Drug Metab Dispos 39:353-362.
Frisoni GB et al. (2013) Imaging markers for Alzheimer disease: which vs how. Neurology 81:487-500.
Furukawa K, Okamura N, Tashiro M, Waragai M, Furumoto S, Iwata R, Yanai K, Kudo Y, Arai H (2009) Amyloid PET in mild cognitive impairment and Alzheimer’s disease with BF-227: comparison to FDG–PET. Journal of Neurology 257:721-727.
Glass CK, Saijo K, Winner B, Marchetto MC, Gage FH (2010) Mechanisms underlying inflammation in neurodegeneration. Cell 140:918-934.
Groenning M (2010) Binding mode of Thioflavin T and other molecular probes in the context of amyloid fibrils-current status. J Chem Biol 3:1-18.
Haass C, Selkoe DJ (2007) Soluble protein oligomers in neurodegeneration: lessons from the Alzheimer's amyloid beta-peptide. Nat Rev Mol Cell Biol 8:101-112.
Haass C, Schlossmacher MG, Hung AY, Vigo-Pelfrey C, Mellon A, Ostaszewski BL, Lieberburg I, Koo EH, Schenk D, Teplow DB, et al. (1992) Amyloid beta-peptide is produced by cultured cells during normal metabolism. Nature 359:322-325.
Haltia M, Viitanen M, Sulkava R, Ala-Hurula V, Poyhonen M, Goldfarb L, Brown P, Levy E, Houlden H, Crook R, et al. (1994) Chromosome 14-encoded Alzheimer's disease:
genetic and clinicopathological description. Ann Neurol 36:362-367.
Han BH, Zhou M-l, Johnson AW, Singh I, Liao F, Vellimana AK, Nelson JW, Milner E, Cirrito JR, Basak J, Yoo M, Dietrich HH, Holtzman DM, Zipfel GJ (2015)
Contribution of reactive oxygen species to cerebral amyloid angiopathy, vasomotor dysfunction, and microhemorrhage in aged Tg2576 mice. Proceedings of the National Academy of Sciences.
Hardy J, Selkoe DJ (2002) The amyloid hypothesis of Alzheimer's disease: progress and problems on the road to therapeutics. Science 297:353-356.
Harold D et al. (2009) Genome-wide association study identifies variants at CLU and PICALM associated with Alzheimer's disease. Nat Genet 41:1088-1093.
Heneka MT, Golenbock DT, Latz E (2015) Innate immunity in Alzheimer's disease. Nat Immunol 16:229-236.
Herholz K et al. (2002) Discrimination between Alzheimer dementia and controls by automated analysis of multicenter FDG PET. Neuroimage 17:302-316.
Higuchi M (2009) Visualization of brain amyloid and microglial activation in mouse models of Alzheimer's disease. Curr Alzheimer Res 6:137-143.
Hilt D, Gawryl M, Koenig G, Dgetluck N, Moebius HJ (2012) EVP-6124, a selective alpha-7 partial agonist, has positive effects on cognition and clinical function in mild to moderate Alzheimer's disease patients: Results of a six-month, double-blind, placebo controlled, dose ranging study. In: AAIC. Vancouver, Canada.
Hollingworth P et al. (2011) Common variants at ABCA7, MS4A6A/MS4A4E, EPHA1, CD33 and CD2AP are associated with Alzheimer's disease. Nat Genet 43:429-435.
Holmes BB, Furman JL, Mahan TE, Yamasaki TR, Mirbaha H, Eades WC, Belaygorod L, Cairns NJ, Holtzman DM, Diamond MI (2014) Proteopathic tau seeding predicts tauopathy in vivo. Proc Natl Acad Sci U S A 111:E4376-4385.
Huang Y, Mucke L (2012) Alzheimer mechanisms and therapeutic strategies. Cell 148:1204-1222.
Hyman BT, Marzloff K, Arriagada PV (1993) The lack of accumulation of senile plaques or amyloid burden in Alzheimer's disease suggests a dynamic balance between amyloid deposition and resolution. J Neuropathol Exp Neurol 52:594-600.
Ikonomovic MD, Abrahamson EE, Price JC, Hamilton RL, Mathis CA, Paljug WR, Debnath ML, Cohen AD, Mizukami K, DeKosky ST, Lopez OL, Klunk WE (2012) Early AD pathology in a [C-11]PiB-negative case: a PiB-amyloid imaging, biochemical, and immunohistochemical study. Acta Neuropathol 123:433-447.
Ikonomovic MD, Klunk WE, Abrahamson EE, Mathis CA, Price JC, Tsopelas ND, Lopresti BJ, Ziolko S, Bi W, Paljug WR, Debnath ML, Hope CE, Isanski BA, Hamilton RL, DeKosky ST (2008) Post-mortem correlates of in vivo PiB-PET amyloid imaging in a typical case of Alzheimer's disease. Brain 131:1630-1645.
Iqbal K, Liu F, Gong CX, Grundke-Iqbal I (2010) Tau in Alzheimer disease and related tauopathies. Curr Alzheimer Res 7:656-664.
Ittner LM, Gotz J (2011) Amyloid-beta and tau--a toxic pas de deux in Alzheimer's disease. Nat Rev Neurosci 12:65-72.