Abstract
Experimental models of Alzheimer’s disease (AD) are critical to gaining a better understanding of pathogenesis and to assess the potential of novel therapeutic approaches. The most commonly used experimental animal models are transgenic mice that overexpress human genes associated with familial AD (FAD) that result in the formation of amyloid plaques. However, AD is defined by the presence and interplay of both amyloid plaques and neurofibrillary tangle pathology. The track record of success in AD clinical trials thus far has been very poor. In part, this high failure rate has been related to the premature translation of highly successful results in animal models that mirror only limited aspects of AD pathology to humans. A greater understanding of the strengths and weakness of each of the various models and the use of more than one model to evaluate potential therapies would help enhance the success of therapy translation from preclinical studies to patients. In this review, we summarize the pathological features and limitations of the major experimental models of AD, including transgenic mice, transgenic rats, various physiological models of sporadic AD and in vitro human cell culture models.
Similar content being viewed by others
References
Alexander AG, Marfil V, Li C (2014) Use of Caenorhabditis elegans as a model to study Alzheimer’s disease and other neurodegenerative diseases. Front Genet 5:279. doi:10.3389/fgene.2014.00279
Andorfer C, Kress Y, Espinoza M, de Silva R, Tucker KL, Barde YA, Duff K, Davies P (2003) Hyperphosphorylation and aggregation of tau in mice expressing normal human tau isoforms. J Neurochem 86:582–590
Bales KR, Liu F, Wu S, Lin S, Koger D, DeLong C, Hansen JC, Sullivan PM, Paul SM (2009) Human APOE isoform-dependent effects on brain beta-amyloid levels in PDAPP transgenic mice. J Neurosci 29:6771–6779
Bales KR, Verina T, Cummins DJ, Du Y, Dodel RC, Saura J, Fishman CE, DeLong CA, Piccardo P, Petegnief V et al (1999) Apolipoprotein E is essential for amyloid deposition in the APPV717F transgenic mouse model of Alzheimer’s disease. PNAS 96:15233–15238
Bales KR, Verina T, Dodel RC, Du YS, Altstiel L, Bender M, Hyslop P, Johnstone EM, Little SP, Cummins DJ et al (1997) Lack of apolipoprotein E dramatically reduces amyloid β-peptide deposition. Nature Gen 17:263–264
Banik A, Brown RE, Bamburg J, Lahiri DK, Khurana D, Friedland RP, Chen W, Ding Y, Mudher A, Padjen AL et al (2015) Translation of pre-clinical studies into successful clinical trials for Alzheimer’s disease: what are the roadblocks and how can they be overcome? J Alzheimers Dis 47:815–843. doi:10.3233/JAD-150136
Bertram L, Tanzi RE (2012) The genetics of Alzheimer’s disease. Prog Mol Biol Transl Sci 107:79–100
Blennow K, Mattsson N, Scholl M, Hansson O, Zetterberg H (2015) Amyloid biomarkers in Alzheimer’s disease. Trends Pharmacol Sci 36:297–309
Blessed G, Tomlinson BE (1968) The association between quantitative measures of dementia and senile change in the gray matter of elderly subjects. Br J Psychiatry 114:797–811
Bolmont T, Clavaguera F, Meyer-Luehmann M, Herzig MC, Radde R, Staufenbiel M, Lewis J, Hutton M, Tolnay M, Jucker M (2007) Induction of tau pathology by intracerebral infusion of amyloid-β-containing brain extract and by amyloid-β deposition in APP x Tau transgenic mice. Am J Pathol 171:2012–2020
Bons N, Mestre N, Ritchie K, Petter A, Podlisny M, Selkoe D (1994) Identification of amyloid β protein in the brain of the small, short-lived lemurian primate Microcebus murinus. Neurobiol Aging 15:215–220
Bons N, Rieger F, Prudhomme D, Fisher A, Krause KH (2006) Microcebus murinus: a useful primate model for human cerebral aging and Alzheimer’s disease? Genes Brain Behav 5:120–130. doi:10.1111/j.1601-183X.2005.00149.x
Bouleau S, Tricoire H (2015) Drosophila models of Alzheimer’s disease: advances, limits, and perspectives. J Alzheimers Dis 45:1015–1038. doi:10.3233/JAD-142802
Boutajangout A, Wisniewski T (2014) Tau-based therapeutic approaches for Alzheimer’s disease—a mini-review. Gerontology 60:381–385. doi:10.1159/000358875
Braak H, Braak E (1991) Neuropathological staging of Alzheimer-related changes. Acta Neuropathol 82:239–259
Braidy N, Poljak A, Jayasena T, Mansour H, Inestrosa NC, Sachdev PS (2015) Accelerating Alzheimer’s research through ‘natural’ animal models. Curr Opin Psychiatry 28:155–164. doi:10.1097/YCO.0000000000000137
Cacace R, Sleegers K, Van Broeckhoven C (2016) Molecular genetics of early-onset Alzheimer’s disease revisited. Alzheimers Dement 12:733–748. doi:10.1016/j.jalz.2016.01.012
Cairns NJ, Perrin RJ, Franklin EE, Carter D, Vincent B, Xie M, Bateman RJ, Benzinger T, Friedrichsen K, Brooks WS et al (2015) Neuropathologic assessment of participants in two multi-center longitudinal observational studies: the Alzheimer Disease Neuroimaging Initiative (ADNI) and the Dominantly Inherited Alzheimer Network (DIAN). Neuropathology 35:390–400. doi:10.1111/neup.12205
Camus S, Ko WK, Pioli E, Bezard E (2015) Why bother using non-human primate models of cognitive disorders in translational research? Neurobiol Learn Mem 124:123–129. doi:10.1016/j.nlm.2015.06.012
Cash DM, Ridgway GR, Liang Y, Ryan NS, Kinnunen KM, Yeatman T, Malone IB, Benzinger TL, Jack CR Jr, Thompson PM et al (2013) The pattern of atrophy in familial Alzheimer disease: volumetric MRI results from the DIAN study. Neurology 81:1425–1433. doi:10.1212/WNL.0b013e3182a841c6
Castellano JM, Kim J, Stewart FR, Jiang H, De Mattos RB, Patterson BW, Fagan AM, Morris JC, Mawuenyega KG, Cruchaga C et al (2011) Human apoE isoforms differentially regulate brain amyloid-β peptide clearance. Sci Transl Med 3:89ra57
Chambers JK, Kuribayashi H, Ikeda S, Une Y (2010) Distribution of neprilysin and deposit patterns of Abeta subtypes in the brains of aged squirrel monkeys (Saimiri sciureus). Amyloid 17:75–82. doi:10.3109/13506129.2010.483119
Choi SH, Kim YH, Hebisch M, Sliwinski C, Lee S, D’Avanzo C, Chen H, Hooli B, Asselin C, Muffat J et al (2014) A three-dimensional human neural cell culture model of Alzheimer’s disease. Nature 515:274–278. doi:10.1038/nature13800
Cohen RM, Rezai-Zadeh K, Weitz TM, Rentsendorj A, Gate D, Spivak I, Bholat Y, Vasilevko V, Glabe CG, Breunig JJ et al (2013) A transgenic Alzheimer rat with plaques, tau pathology, behavioral impairment, oligomeric abeta, and frank neuronal loss. J Neurosci 33:6245–6256. doi:10.1523/JNEUROSCI.3672-12.2013
Crary JF, Trojanowski JQ, Schneider JA, Abisambra JF, Alafuzoff I, Arnold SE, Atterns J, Beach TG, Cairns NJ, Dickson DW et al (2014) Primary age-related tauopathy (PART): a common pathology associated with human aging. Acta Neuropathol 128:755–766
Cummings BJ, Pike CJ, Shankle R, Cotman CW (1996) Beta-amyloid deposition and other measures of neuropathology predict cognitive status in Alzheimer’s disease. Neurobiol Aging 17:921–933
Cummings JL, Morstorf T, Zhong K (2014) Alzheimer’s disease drug-development pipeline: few candidates, frequent failures. Alzheimers Res Ther 6:37. doi:10.1186/alzrt269
Cuyvers E, Sleegers K (2016) Genetic variations underlying Alzheimer’s disease: evidence from genome-wide association studies and beyond. Lancet Neurol 15:857–868. doi:10.1016/S1474-4422(16)00127-7
Davis J, Xu F, Deane R, Romanov G, Previti ML, Zeigler K, Zlokovic BV, van Nostrand WE (2004) Early-onset and robust cerebral microvascular accumulation of amyloid β-protein in transgenic mice expressing low levels of a vasculotropic Dutch/Iowa mutant form of amyloid β-protein precursor. J Biol Chem 279:20296–20306
Davis PR, Head E (2014) Prevention approaches in a preclinical canine model of Alzheimer’s disease: benefits and challenges. Front Pharmacol 5:47. doi:10.3389/fphar.2014.00047
Dhenain M, Michot JL, Privat N, Picq JL, Boller F, Duyckaerts C, Volk A (2000) MRI description of cerebral atrophy in mouse lemur primates. Neurobiol Aging 21:81–88
Do Carmo S, Cuello AC (2013) Modeling Alzheimer’s disease in transgenic rats. Mol Neurodegener 8:37. doi:10.1186/1750-1326-8-37
Drummond ES, Muhling J, Martins RN, Wijaya LK, Ehlert EM, Harvey AR (2013) Pathology associated with AAV mediated expression of beta amyloid or C100 in adult mouse hippocampus and cerebellum. PLoS One 8:e59166. doi:10.1371/journal.pone.0059166
Dujardin S, Colin M, Buee L (2015) Invited review: animal models of tauopathies and their implications for research/translation into the clinic. Neuropathol Appl Neurobiol 41:59–80. doi:10.1111/nan.12200
Duyckaerts C (2011) Tau pathology in children and young adults: can you still be unconditionally baptist? Acta Neuropathol 121:145–147
Elfenbein HA, Rosen RF, Stephens SL, Switzer RC, Smith Y, Pare J, Mehta PD, Warzok R, Walker LC (2007) Cerebral beta-amyloid angiopathy in aged squirrel monkeys. Histol Histopathol 22:155–167
Esh C, Patton L, Kalback W, Kokjohn TA, Lopez J, Brune D, Newell AJ, Beach T, Schenk D, Games D et al (2005) Altered APP processing in PDAPP (Val717 –>Phe) transgenic mice yields extended-length Aβ peptides. Biochemistry 44:13807–13819. doi:10.1021/bi051213+
Fernandez-Funez P, de Mena L, Rincon-Limas DE (2015) Modeling the complex pathology of Alzheimer’s disease in Drosophila. Exp Neurol 274:58–71. doi:10.1016/j.expneurol.2015.05.013
Frost JL, Le KX, Cynis H, Ekpo E, Kleinschmidt M, Palmour RM, Ervin FR, Snigdha S, Cotman CW, Saido TC et al (2013) Pyroglutamate-3 amyloid-beta deposition in the brains of humans, non-human primates, canines, and Alzheimer disease-like transgenic mouse models. Am J Pathol 183:369–381
Fryer JD, Simmons K, Parsadanian M, Bales KR, Paul SM, Sullivan PM, Holtzman DM (2005) Human apolipoprotein E4 alters the amyloid-beta 40:42 ratio and promotes the formation of cerebral amyloid angiopathy in an amyloid precursor protein transgenic model. J Neurosci 25:2803–2810
Fryer JD, Taylor JW, DeMattos RB, Bales KR, Paul SM, Parsadanian M, Holtzman DM (2003) Apolipoprotein E markedly facilitates age-dependent cerebral amyloid angiopathy and spontaneous hemorrhage in amyloid precursor protein Transgenic mice. J Neurosci 23:7889–7896
Games D, Adams D, Alessandrini R, Barbour R, Berthelette P, Blackwell C, Carr T, Clemens J, Donaldson T, Gillespie F et al (1995) Alzheimer-type neuropathology in transgenic mice overexpressing V717F β-amyloid precursor protein. Nature 373:523–527
Gearing M, Rebeck GW, Hyman BT, Tigges J, Mirra SS (1994) Neuropathology and apolipoprotein E profile of aged chimpanzees: implications for Alzheimer disease. Proc Natl Acad Sci USA 91:9382–9386
Gearing M, Tigges J, Mori H, Mirra SS (1997) β-Amyloid (Aβ) deposition in the brains of aged orangutans. Neurobiol Aging 18:139–146
Ghosal K, Vogt DL, Liang M, Shen Y, Lamb BT, Pimplikar SW (2009) Alzheimer’s disease-like pathological features in transgenic mice expressing the APP intracellular domain. Proc Natl Acad Sci USA 106:18367–18372. doi:10.1073/pnas.0907652106
Giannakopoulos P, Kovari E, Gold G, von Gunten A, Hof PR, Bouras C (2009) Pathological substrates of cognitive decline in Alzheimer’s disease. Front Neurol Neurosci 24:20–29. doi:10.1159/000197881
Giannakopoulos P, Silhol S, Jallageas V, Mallet J, Bons N, Bouras C, Delaère P (1997) Quantitative analysis of tau protein-immunoreactive accumulations and β amyloid protein deposits in the cerebral cortex of the mouse lemur, Microcebus murinus. Acta Neuropathol 94:131–139
Gold G, Bouras C, Kovari E, Canuto A, Glaria BG, Malky A, Hof PR, Michel JP, Giannakopoulos P (2000) Clinical validity of Braak neuropathological staging in the oldest-old. Acta Neuropathol 99:579–582 (discussion 583–574)
Gotz J, Ittner LM (2008) Animal models of Alzheimer’s disease and frontotemporal dementia. Nat Rev Neurosci 9:532–544
Gouras GK, Tampellini D, Takahashi RH, Capetillo-Zarate E (2010) Intraneuronal beta-amyloid accumulation and synapse pathology in Alzheimer’s disease. Acta Neuropathol 119:523–541. doi:10.1007/s00401-010-0679-9
Grueninger F, Bohrmann B, Czech C, Ballard TM, Frey JR, Weidensteiner C, von Kienlin M, Ozmen L (2010) Phosphorylation of Tau at S422 is enhanced by Abeta in TauPS2APP triple transgenic mice. Neurobiol Dis 37:294–306. doi:10.1016/j.nbd.2009.09.004
Guerreiro R, Hardy J (2014) Genetics of Alzheimer’s disease. Neurotherapeutics 11:432–437
Hannan SB, Drager NM, Rasse TM, Voigt A, Jahn TR (2016) Cellular and molecular modifier pathways in tauopathies: the big picture from screening invertebrate models. J Neurochem 137:12–25. doi:10.1111/jnc.13532
Hartig W, Bruckner G, Schmidt C, Brauer K, Bodewitz G, Turner JD, Bigl V (1997) Co-localization of beta-amyloid peptides, apolipoprotein E and glial markers in senile plaques in the prefrontal cortex of old rhesus monkeys. Brain Res 751:315–322
Hartley D, Blumenthal T, Carrillo M, DiPaolo G, Esralew L, Gardiner K, Granholm AC, Iqbal K, Krams M, Lemere CA et al (2015) Down syndrome and Alzheimer’s disease: common pathways, common goals. Alzheimer’s Dement 11:700–709
Heilbroner PL, Kemper TL (1990) The cytoarchitectonic distribution of senile plaques in three aged monkeys. Acta Neuropathol 81:60–65
Heuer E, Rosen RF, Cintron A, Walker LC (2012) Nonhuman primate models of Alzheimer-like cerebral proteopathy. Curr Pharm Des 18:1159–1169
Holcomb L, Gordon MN, McGowan E, Yu X, Benkovic S, Jantzen P, Saad WK, Mueller R, Morgan D, Sanders S et al (1998) Accelerated Alzheimer-type phenotype in transgenic mice carrying both mutant amyloid precursor protein and presenilin 1 transgenes. Nat Med 4:97–100
Holtzman DM, Bales KR, Tenkova T, Fagan AM, Parsadanian M, Sartorius LJ, Mackey B, Olney J, McKeel D, Wozniak D et al (2000) Apolipoprotein E isoform-dependent amyloid deposition and neuritic degeneration in a mouse model of Alzheimer’s disease. PNAS 97:2892–2897
Holtzman DM, Bales KR, Wu S, Bhat P, Parsadanian M, Fagan AM, Chang LK, Sun Y, Paul SM (1999) Expression of human apolipoprotein E reduces amyloid-beta deposition in a mouse model of Alzheimer’s disease. J Clin Invest 103:R15–R21
Holtzman DM, Fagan AM, Mackey B, Tenkova T, Sartorius L, Paul SM, Bales KR, Hsiao Ashe K, Irizarry MC, Hyman BT (2000) Apolipoprotein E facilitates neuritic and cerebrovascular plaque formation in an Alzheimer’s disease model. Ann Neurol 47:739–747
Hsiao KK, Chapman P, Nilsen S, Eckman C, Harigaya Y, Younkin S, Yang F, Cole G (1996) Correlative memory deficits, Aβ elevation and amyloid plaques in transgenic mice. Science 274:99–102
Huang Y, Mahley RW (2014) Apolipoprotein E: structure and function in lipid metabolism, neurobiology, and Alzheimer’s diseases. Neurobiol Dis 72(Pt A):3–12. doi:10.1016/j.nbd.2014.08.025
Hunter JM, Bowers WJ, Maarouf CL, Mastrangelo MA, Daugs ID, Kokjohn TA, Kalback WM, Luehrs DC, Valla J, Beach TG et al (2011) Biochemical and morphological characterization of the AβPP/PS/tau triple transgenic mouse model and its relevance to sporadic Alzheimer’s disease. J Alzheimers Dis 27:361–376
Hyman BT, Phelps CH, Beach TG, Bigio EH, Cairns NJ, Carrillo MC, Dickson DW, Duyckaerts C, Frosch MP, Masliah E et al (2012) National Institute on Aging-Alzheimer’s Association guidelines for the neuropathologic assessment of Alzheimer’s disease. Alzheimers Dement 8:1–13
Israel MA, Yuan SH, Bardy C, Reyna SM, Mu Y, Herrera C, Hefferan MP, Van Gorp S, Nazor KL, Boscolo FS et al (2012) Probing sporadic and familial Alzheimer’s disease using induced pluripotent stem cells. Nature 482:216–220. doi:10.1038/nature10821
Jack CR Jr, Albert MS, Knopman DS, McKhann GM, Sperling RA, Carrillo MC, Thies B, Phelps CH (2011) Introduction to the recommendations from the National Institute on Aging-Alzheimer’s Association workgroups on diagnostic guidelines for Alzheimer’s disease. Alzheimers Dement 7:257–262
Jellinger KA (2002) Alzheimer disease and cerebrovascular pathology: an update. J Neural Transm 109:813–836
Jones RW (2010) Dimebon disappointment. Alzheimers Res Ther 2:25. doi:10.1186/alzrt49
Joseph-Mathurin N, Dorieux O, Trouche SG, Boutajangout A, Kraska A, Fontes P, Verdier JM, Sigurdsson EM, Mestre-Frances N, Dhenain M (2013) Amyloid β immunization worsens iron deposits in the choroid plexus and cerebral microbleeds. Neurobiol Aging 34:2613–2622. doi:10.1016/j.neurobiolaging.2013.05.013
Kalback W, Watson MD, Kokjohn TA, Kuo YM, Weiss N, Luehrs DC, Lopez J, Brune D, Sisodia SS, Staufenbiel M et al (2002) APP transgenic mice Tg2576 accumulate Aβ peptides that are distinct from the chemically modified and insoluble peptides deposited in Alzheimer’s disease senile plaques. Biochemistry 41:922–928
Kalinin S, Willard SL, Shively CA, Kaplan JR, Register TC, Jorgensen MJ, Polak PE, Rubinstein I, Feinstein DL (2013) Development of amyloid burden in African Green monkeys. Neurobiol Aging 34:2361–2369. doi:10.1016/j.neurobiolaging.2013.03.023
Kamp JA, Moursel LG, Haan J, Terwindt GM, Lesnik Oberstein SA, van Duinen SG, van Roon-Mom WM (2014) Amyloid β in hereditary cerebral hemorrhage with amyloidosis-Dutch type. Rev Neurosci 25:641–651. doi:10.1515/revneuro-2014-0008
Karch CM, Cruchaga C, Goate AM (2014) Alzheimer’s disease genetics: from the bench to the clinic. Neuron 83:11–26
Karch CM, Goate AM (2015) Alzheimer’s disease risk genes and mechanisms of disease pathogenesis. Biol Psychiatry 77:43–51. doi:10.1016/j.biopsych.2014.05.006
Kim DH, Yeo SH, Park JM, Choi JY, Lee TH, Park SY, Ock MS, Eo J, Kim HS, Cha HJ (2014) Genetic markers for diagnosis and pathogenesis of Alzheimer’s disease. Gene 545:185–193
Kim YH, Choi SH, D’Avanzo C, Hebisch M, Sliwinski C, Bylykbashi E, Washicosky KJ, Klee JB, Brustle O, Tanzi RE et al (2015) A 3D human neural cell culture system for modeling Alzheimer’s disease. Nat Protoc 10:985–1006. doi:10.1038/nprot.2015.065
Kimura N, Nakamura S, Goto N, Narushima E, Hara I, Shichiri S, Saitou K, Nose M, Hayashi T, Kawamura S et al (2001) Senile plaques in an aged western lowland gorilla. Exp Anim 50:77–81
Knight EM, Kim SH, Kottwitz JC, Hatami A, Albay R, Suzuki A, Lublin A, Alberini CM, Klein WL, Szabo P et al (2016) Effective anti-Alzheimer Aβ therapy involves depletion of specific Aβ oligomer subtypes. Neurol Neuroimmunol Neuroinflamm 3:e237. doi:10.1212/NXI.0000000000000237
Knopman DS (2015) Is dominantly inherited Alzheimer disease a clone of sporadic Alzheimer disease? Neurology 85:750–751. doi:10.1212/WNL.0000000000001897
Knopman DS, Jack CR Jr, Lundt ES, Weigand SD, Vemuri P, Lowe VJ, Kantarci K, Gunter JL, Senjem ML, Mielke MM et al (2016) Evolution of neurodegeneration-imaging biomarkers from clinically normal to dementia in the Alzheimer disease spectrum. Neurobiol Aging 46:32–42. doi:10.1016/j.neurobiolaging.2016.06.003
Kondo T, Asai M, Tsukita K, Kutoku Y, Ohsawa Y, Sunada Y, Imamura K, Egawa N, Yahata N, Okita K et al (2013) Modeling Alzheimer’s disease with iPSCs reveals stress phenotypes associated with intracellular Abeta and differential drug responsiveness. Cell Stem Cell 12:487–496. doi:10.1016/j.stem.2013.01.009
Kraska A, Dorieux O, Picq JL, Petit F, Bourrin E, Chenu E, Volk A, Perret M, Hantraye P, Mestre-Frances N et al (2011) Age-associated cerebral atrophy in mouse lemur primates. Neurobiol Aging 32:894–906. doi:10.1016/j.neurobiolaging.2009.05.018
Kumar S, Rezaei-Ghaleh N, Terwel D, Thal DR, Richard M, Hoch M, Mc Donald JM, Wullner U, Glebov K, Heneka MT et al (2011) Extracellular phosphorylation of the amyloid beta-peptide promotes formation of toxic aggregates during the pathogenesis of Alzheimer’s disease. EMBO J 30:2255–2265. doi:10.1038/emboj.2011.138
Kuo YM, Kokjohn TA, Beach TG, Sue LI, Brune D, Lopez JC, Kalback WM, Abramowski D, Sturchler-Pierrat C, Staufenbiel M et al (2001) Comparitive analysis of amyloid-beta chemical structure and amyloid plaque morphology of transgenic mouse and Alzheimer’s disease brains. JBC 276:12991–12998
Kuszczyk MA, Sanchez S, Pankiewicz J, Kim J, Duszczyk M, Guridi M, Asuni AA, Sullivan PM, Holtzman DM, Sadowski MJ (2013) Blocking the interaction between apolipoprotein E and Aβ reduces intraneuronal accumulation of Aβ and inhibits synaptic degeneration. Am J Pathol 182:1750–1768
Lawlor PA, Bland RJ, Das P, Price RW, Holloway V, Smithson L, Dicker BL, During MJ, Young D, Golde TE (2007) Novel rat Alzheimer’s disease models based on AAV-mediated gene transfer to selectively increase hippocampal Aβ levels. Mol Neurodegener 2:11. doi:10.1186/1750-1326-2-11
Lemere CA, Beierschmitt A, Iglesias M, Spooner ET, Bloom JK, Leverone JF, Zheng JB, Seabrook TJ, Louard D, Li D et al (2004) Alzheimer’s disease aβ vaccine reduces central nervous system aβ levels in a non-human primate, the Caribbean vervet. Am J Pathol 165:283–297
Lemere CA, Iglesias M, Spooner ET, Bloom JK, Leverone JF, Li D, Zheng JB, Seabrook TJ, Selkoe D, Ervin FR et al (2003) Aβ immunization in aged vervet monkeys reduces Aβ levels in brain and CSF. Soc Neurosci Abst 133(5):5
Leon WC, Canneva F, Partridge V, Allard S, Ferretti MT, DeWilde A, Vercauteren F, Atifeh R, Ducatenzeiler A, Klein W et al (2010) A novel transgenic rat model with a full Alzheimer’s-like amyloid pathology displays pre-plaque intracellular amyloid-beta-associated cognitive impairment. J Alzheimer’s Dis 20:113–126. doi:10.3233/JAD-2010-1349
Lewis J, Dickson D, Lin WL, Chisholm L, Corral A, Jones G, Yen SH, Sahara N, Skipper L, Yager D et al (2001) Enhanced neurofibrillary degeneration in transgenic mice expressing mutant tau and APP. Science 293:1487–1491
Lewis J, McGowan E, Rockwood J, Melrose H, Nacharaju P, Van Slegtenhorst M, Gwinn-Hardy K, Murphy MP, Baker M, Yu X et al (2000) Neurofibrillary tangles, amyotrophy and progressive motor disturbance in mice expressing mutant (P301L) tau protein. Nat Genet 25:402–405
Li H, Guo Q, Inoue T, Polito VA, Tabuchi K, Hammer RE, Pautler RG, Taffet GE, Zheng H (2014) Vascular and parenchymal amyloid pathology in an Alzheimer disease knock-in mouse model: interplay with cerebral blood flow. Mol Neurodegener 9:28. doi:10.1186/1750-1326-9-28
Liao F, Zhang TJ, Jiang H, Lefton KB, Robinson GO, Vassar R, Sullivan PM, Holtzman DM (2015) Murine versus human apolipoprotein E4: differential facilitation of and co-localization in cerebral amyloid angiopathy and amyloid plaques in APP transgenic mouse models. Acta Neuropathol Commun 3:70. doi:10.1186/s40478-015-0250-y
Liu L, Orozco IJ, Planel E, Wen Y, Bretteville A, Krishnamurthy P, Wang L, Herman M, Figueroa H, Yu WH et al (2008) A transgenic rat that develops Alzheimer’s disease-like amyloid pathology, deficits in synaptic plasticity and cognitive impairment. Neurobiol Dis 31:46–57. doi:10.1016/j.nbd.2008.03.005
Martin LJ, Pardo CA, Cork LC, Price DL (1994) Synaptic pathology and glial responses to neuronal injury precede the formation of senile plaques and amyloid deposits in the aging cerebral cortex. Am J Pathol 145:1358–1381
McKee AC, Kosik KS, Kowall NW (1991) Neuritic pathology and dementia in Alzheimer’s disease. Ann Neurol 30:156–165. doi:10.1002/ana.410300206
Mestre-Frances N, Keller E, Calenda A, Barelli H, Checler F, Bons N (2000) Immunohistochemical analysis of cerebral cortical and vascular lesions in the primate Microcebus murinus reveal distinct amyloid β1–42 and β1–40 immunoreactivity profiles. Neurobiol Dis 7:1–8. doi:10.1006/nbdi.1999.0270
Montine TJ, Phelps CH, Beach TG, Bigio EH, Cairns NJ, Dickson DW, Duyckaerts C, Frosch MP, Masliah E, Mirra SS et al (2012) National Institute on Aging-Alzheimer’s Association guidelines for the neuropathologic assessment of Alzheimer’s disease: a practical approach. Acta Neuropathol 123:1–11
Mucke L, Masliah E, Yu GQ, Mallory M, Rockenstein EM, Tatsuno G, Hu K, Kholodenko D, Johnson-Wood K, McConlogue L (2000) High-level neuronal expression of aβ 1-42 in wild-type human amyloid protein precursor transgenic mice: synaptotoxicity without plaque formation. J Neurosci 20:4050–4058
Muratore CR, Rice HC, Srikanth P, Callahan DG, Shin T, Benjamin LN, Walsh DM, Selkoe DJ, Young-Pearse TL (2014) The familial Alzheimer’s disease APPV717I mutation alters APP processing and Tau expression in iPSC-derived neurons. Hum Mol Genet 23:3523–3536. doi:10.1093/hmg/ddu064
Nelson PT, Alafuzoff I, Bigio EH, Bouras C, Braak H, Cairns N, Davies P, Tredici KD, Duyckaerts C, Frosch MP et al (2012) Correlation of Alzheimer’s disease neuropathologic changes with cognitive status: a review of the literature. JNEN 71:362–381
Nelson PT, Braak H, Markesbery WR (2009) Neuropathology and cognitive impairment in Alzheimer disease: a complex but coherent relationship. J Neuropathol Exp Neurol 68:1–14. doi:10.1097/NEN.0b013e3181919a48
Newman M, Ebrahimie E, Lardelli M (2014) Using the zebrafish model for Alzheimer’s disease research. Front Genet 5:189. doi:10.3389/fgene.2014.00189
Nikolaev A, McLaughlin T, O’Leary DD, Tessier-Lavigne M (2009) APP binds DR6 to trigger axon pruning and neuron death via distinct caspases. Nature 457:981–989. doi:10.1038/nature07767
Nisbet RM, Polanco JC, Ittner LM, Gotz J (2015) Tau aggregation and its interplay with amyloid-beta. Acta Neuropathol 129:207–220. doi:10.1007/s00401-014-1371-2
Oakley H, Cole SL, Logan S, Maus E, Shao P, Craft J, Guillozet-Bongaarts A, Ohno M, Disterhoft J, Van EL et al (2006) 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 26:10129–10140
Oddo S, Caccamo A, Kitazawa M, Tseng BP, LaFerla FM (2003) Amyloid deposition precedes tangle formation in a triple transgenic model of Alzheimer’s disease. Neurobiol Aging 24:1063–1070
Oddo S, Caccamo A, Shepherd JD, Murphy MP, Golde TE, Kayed R, Metherate R, Mattson MP, Akbari Y, LaFerla FM (2003) Triple-transgenic model of Alzheimer’s disease with plaques and tangles: intracellular Aβ and synaptic dysfunction. Neuron 39:409–421
Pankiewicz JE, Guridi M, Kim J, Asuni AA, Sanchez S, Sullivan PM, Holtzman DM, Sadowski MJ (2014) Blocking the apoE/Aβ interaction ameliorates Aβ-related pathology in APOE ε2 and ε4 targeted replacement Alzheimer model mice. Acta Neuropathol Commun 2:75. doi:10.1186/s40478-014-0075-0
Paquet D, Bhat R, Sydow A, Mandelkow EM, Berg S, Hellberg S, Falting J, Distel M, Koster RW, Schmid B et al (2009) A zebrafish model of tauopathy allows in vivo imaging of neuronal cell death and drug evaluation. J Clin Invest 119:1382–1395. doi:10.1172/JCI37537
Perez SE, Raghanti MA, Hof PR, Kramer L, Ikonomovic MD, Lacor PN, Erwin JM, Sherwood CC, Mufson EJ (2013) Alzheimer’s disease pathology in the neocortex and hippocampus of the western lowland gorilla (Gorilla gorilla gorilla). J Comp Neurol 521:4318–4338. doi:10.1002/cne.23428
Perez SE, Sherwood CC, Cranfield MR, Erwin JM, Mudakikwa A, Hof PR, Mufson EJ (2016) Early Alzheimer’s disease-type pathology in the frontal cortex of wild mountain gorillas (Gorilla beringei beringei). Neurobiol Aging 39:195–201. doi:10.1016/j.neurobiolaging.2015.12.017
Picq JL, Aujard F, Volk A, Dhenain M (2012) Age-related cerebral atrophy in nonhuman primates predicts cognitive impairments. Neurobiol Aging 33:1096–1109. doi:10.1016/j.neurobiolaging.2010.09.009
Potter H, Wisniewski T (2012) Apolipoprotein E: essential catalyst of the Alzheimer amyloid cascade. Int J Alzheimer’s Dis 2012:489428
Prins ND, Visser PJ, Scheltens P (2010) Can novel therapeutics halt the amyloid cascade? Alzheimers Res Ther 2:5
Puzzo D, Gulisano W, Palmeri A, Arancio O (2015) Rodent models for Alzheimer’s disease drug discovery. Expert Opin Drug Discov 10:703–711. doi:10.1517/17460441.2015.1041913
Radde R, Bolmont T, Kaeser SA, Coomaraswamy J, Lindau D, Stoltze L, Calhoun ME, Jaggi F, Wolburg H, Gengler S et al (2006) Aβ42-driven cerebral amyloidosis in transgenic mice reveals early and robust pathology. EMBO Rep 7:940–946
Raja WK, Mungenast AE, Lin YT, Ko T, Abdurrob F, Seo J, Tsai LH (2016) Self-organizing 3D human neural tissue derived from induced pluripotent stem cells recapitulate Alzheimer’s disease phenotypes. PLoS One 11:e0161969. doi:10.1371/journal.pone.0161969
Rebeck GW, Hoe HS, Moussa CE (2010) β-Amyloid1-42 Gene Transfer Model Exhibits Intraneuronal Amyloid, Gliosis, Tau Phosphorylation, and Neuronal Loss. J Biol Chem 285:7440–7446. doi:10.1074/jbc.M109.083915
Ribe EM, Perez M, Puig B, Gich I, Lim F, Cuadrado M, Sesma T, Catena S, Sanchez B, Nieto M et al (2005) Accelerated amyloid deposition, neurofibrillary degeneration and neuronal loss in double mutant APP/tau transgenic mice. Neurobiol Dis 20:814–822. doi:10.1016/j.nbd.2005.05.027
Rijal UA, Kosterin I, Kumar S, Von Arnim CA, Yamaguchi H, Fandrich M, Walter J, Thal DR (2014) Biochemical stages of amyloid-beta peptide aggregation and accumulation in the human brain and their association with symptomatic and pathologically preclinical Alzheimer’s disease. Brain 137:887–903
Robinson JL, Geser F, Corrada MM, Berlau DJ, Arnold SE, Lee VM, Kawas CH, Trojanowski JQ (2011) Neocortical and hippocampal amyloid-beta and tau measures associate with dementia in the oldest-old. Brain 134:3708–3715. doi:10.1093/brain/awr308
Rosen RF, Farberg AS, Gearing M, Dooyema J, Long PM, Anderson DC, Davis-Turak J, Coppola G, Geschwind DH, Pare JF et al (2008) Tauopathy with paired helical filaments in an aged chimpanzee. J Comp Neurol 509:259–270. doi:10.1002/cne.21744
Rosen RF, Tomidokoro Y, Farberg AS, Dooyema J, Ciliax B, Preuss TM, Neubert TA, Ghiso JA, LeVine H 3rd, Walker LC (2016) Comparative pathobiology of beta-amyloid and the unique susceptibility of humans to Alzheimer’s disease. Neurobiol Aging 44:185–196. doi:10.1016/j.neurobiolaging.2016.04.019
Rosen RF, Walker LC, Levine H 3rd (2011) PIB binding in aged primate brain: enrichment of high-affinity sites in humans with Alzheimer’s disease. Neurobiol Aging 32:223–234. doi:10.1016/j.neurobiolaging.2009.02.011
Ryman DC, Acosta-Baena N, Aisen PS, Bird T, Danek A, Fox NC, Goate A, Frommelt P, Ghetti B, Langbaum JB et al (2014) Symptom onset in autosomal dominant Alzheimer disease: a systematic review and meta-analysis. Neurology 83:253–260. doi:10.1212/WNL.0000000000000596
Sadowski M, Pankiewicz J, Scholtzova H, Mehta P, Prelli F, Quartermain D, Wisniewski T (2006) Blocking the apolipoproteinE/Amyloid β interaction reduces the parenchymal and vascular amyloid-β deposition and prevents memory deficit in AD transgenic mice. PNAS 103:18787–18792
Saito T, Matsuba Y, Mihira N, Takano J, Nilsson P, Itohara S, Iwata N, Saido TC (2014) Single App knock-in mouse models of Alzheimer’s disease. Nat Neurosci 17:661–663. doi:10.1038/nn.3697
Saito T, Matsuba Y, Yamazaki N, Hashimoto S, Saido TC (2016) Calpain activation in Alzheimer’s model mice is an artifact of APP and presenilin over-expression. J Neurosci 36:9933–9936. doi:10.1523/JNEUROSCI.1907-16.2016
Salazar C, Valdivia G, Ardiles AO, Ewer J, Palacios AG (2016) Genetic variants associated with neurodegenerative Alzheimer disease in natural models. Biol Res 49:14. doi:10.1186/s40659-016-0072-9
Salloway S, Sperling R, Fox NC, Blennow K, Klunk W, Raskind M, Sabbagh M, Honig LS, Porsteinsson AP, Ferris S et al (2014) Two phase 3 trials of bapineuzumab in mild-to-moderate Alzheimer’s disease. N Engl J Med 370:322–333
Salloway S, Sperling R, Gilman S, Fox NC, Blennow K, Raskind M, Sabbagh M, Honig LS, Doody R, Van Dyck CH et al (2009) A phase 2 multiple ascending dose trial of bapineuzumab in mild to moderate Alzheimer disease. Neurology 73:2061–2070
Sani S, Traul D, Klink A, Niaraki N, Gonzalo-Ruiz A, Wu CK, Geula C (2003) Distribution, progression and chemical composition of cortical amyloid-beta deposits in aged rhesus monkeys: similarities to the human. Acta Neuropathol 105:145–156. doi:10.1007/s00401-002-0626-5
Santacruz K, Lewis J, Spires T, Paulson J, Kotilinek L, Ingelsson M, Guimaraes A, DeTure M, Ramsden M, McGowan E et al (2005) Tau suppression in a neurodegenerative mouse model improves memory function. Science 309:476–481
Scheltens P, Blennow K, Breteler MM, de Strooper B, Frisoni GB, Salloway S, Van der Flier WM (2016) Alzheimer’s disease. Lancet 388:505–517. doi:10.1016/S0140-6736(15)01124-1
Schmidt F, Boltze J, Jager C, Hofmann S, Willems N, Seeger J, Hartig W, Stolzing A (2015) Detection and quantification of β-amyloid, pyroglutamyl Aβ, and tau in aged canines. J Neuropathol Exp Neurol 74:912–923. doi:10.1097/NEN.0000000000000230
Schneider I, Reverse D, Dewachter I, Ris L, Caluwaerts N, Kuiperi C, Gilis M, Geerts H, Kretzschmar H, Godaux E et al (2001) Mutant presenilins disturb neuronal calcium homeostasis in the brain of transgenic mice, decreasing the threshold for excitotoxicity and facilitating long-term potentiation. J Biol Chem 276:11539–11544. doi:10.1074/jbc.M010977200
Schneider LS, Mangialasche F, Andreasen N, Feldman H, Giacobini E, Jones R, Mantua V, Mecocci P, Pani L, Winblad B et al (2014) Clinical trials and late-stage drug development for Alzheimer’s disease: an appraisal from 1984 to 2014. J Intern Med 275:251–283
Scholtzova H, Nehete P, Nehete BP, Mallory M, Cho EH, Holmes A, Park J, Wren MS, Pardington P, Gupta G et al (2015) Toll-like receptor 9 stimulation via CpG ODN in a non-human primate model of sporadic cerebral amyloid angiopathy. Alz Dementia 11:P618
Scholtzova H, Williams L, Nehete P, Sabado R, Holmes A, Wisniewski T (2013) Innate immunity stimulation via TLR9 in a non-human primate model of sporadic cerebral amyloid angiopathy. Alz Dementia 9:p508
Schultz C, Hubbard GB, Rub U, Braak E, Braak H (2000) Age-related progression of tau pathology in brains of baboons. Neurobiol Aging 21:905–912
Schutt T, Helboe L, Pedersen LO, Waldemar G, Berendt M, Pedersen JT (2016) Dogs with cognitive dysfunction as a spontaneous model for early Alzheimer’s disease: a translational study of neuropathological and inflammatory markers. J Alzheimers Dis 52:433–449. doi:10.3233/JAD-151085
Selkoe DJ, Hardy J (2016) The amyloid hypothesis of Alzheimer’s disease at 25 years. EMBO Mol Med 8:595–608. doi:10.15252/emmm.201606210
Sevigny J, Chiao P, Bussiere T, Weinreb PH, Williams L, Maier M, Dunstan R, Salloway S, Chen T, Ling Y et al (2016) The antibody aducanumab reduces Aβ plaques in Alzheimer’s disease. Nature 537:50–56. doi:10.1038/nature19323
Shah P, Lal N, Leung E, Traul DE, Gonzalo-Ruiz A, Geula C (2010) Neuronal and axonal loss are selectively linked to fibrillar amyloid-β within plaques of the aged primate cerebral cortex. Am J Pathol 177:325–333. doi:10.2353/ajpath.2010.090937
Shinohara M, Fujioka S, Murray ME, Wojtas A, Baker M, Rovelet-Lecrux A, Rademakers R, Das P, Parisi JE, Graff-Radford NR et al (2014) Regional distribution of synaptic markers and APP correlate with distinct clinicopathological features in sporadic and familial Alzheimer’s disease. Brain 137:1533–1549. doi:10.1093/brain/awu046
Smolek T, Madari A, Farbakova J, Kandrac O, Jadhav S, Cente M, Brezovakova V, Novak M, Zilka N (2016) Tau hyperphosphorylation in synaptosomes and neuroinflammation are associated with canine cognitive impairment. J Comp Neurol 524:874–895. doi:10.1002/cne.23877
Steffen J, Krohn M, Paarmann K, Schwitlick C, Bruning T, Marreiros R, Muller-Schiffmann A, Korth C, Braun K, Pahnke J (2016) Revisiting rodent models: octodon degus as Alzheimer’s disease model? Acta Neuropathol Commun 4:91. doi:10.1186/s40478-016-0363-y
Struble RG, Price DL Jr, Cork LC, Price DL (1985) Senile plaques in cortex of aged normal monkeys. Brain Res 361:267–275
Sturchler-Pierrat C, Abramowski D, Duke M, Wiederhold KH, Mistl C, Rothacher S, Ledermann B, Bürki K, Frey P, Paganetti PA et al (1997) Two amyloid precursor protein transgenic mouse models with Alzheimer disease-like pathology. Proc Natl Acad Sci USA 94:13287–13292
Sturchler-Pierrat C, Staufenbiel M (2000) Pathogenic mechanisms of Alzheimer’s disease analyzed in the APP23 transgenic mouse model. Ann N Y Acad Sci 920:134–139
Takahashi K, Okita K, Nakagawa M, Yamanaka S (2007) Induction of pluripotent stem cells from fibroblast cultures. Nat Protoc 2:3081–3089. doi:10.1038/nprot.2007.418
Takeuchi A, Irizarry MC, Duff K, Saido T, Hsiao Ashe K, Hasegawa H, Mann DM, Hyman BT, Iwatsubo T (2000) Age-related amyloid & #x03B2; deposition in transgenic mice overexpressing both Alzheimer mutant presenilin 1 and amylo β precursor protein swedish mutant is not associated with global neuronal loss. AJP 157:331–339
Tanzi RE, Gusella JF, Watkins PC, Bruns GA, St. George Hyslop P, VanKeuren ML, Patterson D, Pagan S, Kurnit DM, Neve RL (1987) Amyloid & #x03B2;-protein gene: cDNA, mRNA distribution and genetic linkage near the Alzheimer’s locus. Science 235:880–884
Tellechea P, Pujol N, Esteve-Belloch P, Echeveste B, Garcia-Eulate MR, Arbizu J, Riverol M (2015) Early- and late-onset Alzheimer disease: are they the same entity? Neurologia. doi:10.1016/j.nrl.2015.08.002
Thal DR, Rub U, Orantes M, Braak H (2002) Phases of A beta-deposition in the human brain and its relevance for the development of AD. Neurology 58:1791–1800
Thal DR, Walter J, Saido TC, Fandrich M (2015) Neuropathology and biochemistry of Aβ and its aggregates in Alzheimer’s disease. Acta Neuropathol 129:167–182. doi:10.1007/s00401-014-1375-y
Tomiyama T, Matsuyama S, Iso H, Umeda T, Takuma H, Ohnishi K, Ishibashi K, Teraoka R, Sakama N, Yamashita T et al (2010) A mouse model of amyloid β oligomers: their contribution to synaptic alteration, abnormal tau phosphorylation, glial activation, and neuronal loss in vivo. J Neurosci 30:4845–4856
Tomlinson BE, Blessed G, Roth M (1970) Observations on the brains of demented old people. J Neurol Sci 11:205–242
Trouche SG, Asuni A, Rouland S, Wisniewski T, Frangione B, Verdier JM, Sigurdsson EM, Mestre-Frances N (2009) Antibody response and plasma Aβ1–40 in young Microcebus murinus primates immunized with Aβ1–42 and its derivatives. Vaccine 27:957–964
Ulrich JD, Holtzman DM (2016) TREM2 Function in Alzheimer’s disease and neurodegeneration. ACS Chem Neurosci 7:420–427. doi:10.1021/acschemneuro.5b00313
Umeda T, Maekawa S, Kimura T, Takashima A, Tomiyama T, Mori H (2014) Neurofibrillary tangle formation by introducing wild-type human tau into APP transgenic mice. Acta Neuropathol 127:685–698. doi:10.1007/s00401-014-1259-1
Uno H, Alsum PB, Dong S, Richardson R, Zimbric ML, Thieme CS, Houser WD (1996) Cerebral amyloid angiopathy and plaques, and visceral amyloidosis in aged macaques. Neurobiol Aging 17:275–281
Uno H, Walker LC (1993) The age of biosenescence and the incidence of cerebral beta-amyloidosis in aged captive rhesus monkeys. Ann N Y Acad Sci 695:232–235
Viola KL, Klein WL (2015) Amyloid beta oligomers in Alzheimer’s disease pathogenesis, treatment, and diagnosis. Acta Neuropathol 129:183–206
Walker LC, Kitt CA, Schwam E, Buckwald B, Garcia F, Sepinwall J, Price DL (1987) Senile plaques in aged squirrel monkeys. Neurobiol Aging 8:291–296
Walker LC, Masters C, Beyreuther K, Price DL (1990) Amyloid in the brains of aged squirrel monkeys. Acta Neuropathol 80:381–387
Webster SJ, Bachstetter AD, Nelson PT, Schmitt FA, Van Eldik LJ (2014) Using mice to model Alzheimer’s dementia: an overview of the clinical disease and the preclinical behavioral changes in 10 mouse models. Front Genet 5:88. doi:10.3389/fgene.2014.00088
Wingo TS, Lah JJ, Levey AI, Cutler DJ (2012) Autosomal recessive causes likely in early-onset Alzheimer disease. Arch Neurol 69:59–64
Wisniewski T, Drummond E (2016) Developing therapeutic vaccines against Alzheimer’s disease. Expert Rev Vaccines 15:401–415. doi:10.1586/14760584.2016.1121815
Wisniewski T, Goni F (2015) Immunotherapeutic Approaches for Alzheimer’s Disease. Neuron 85:1162–1176
Wisniewski T, Sigurdsson EM (2010) Murine models of Alzheimer’s disease and their use in developing immunotherapies. Biochim Biophys Acta Mol Basis Dis 1802:847–859
Xu G, Ran Y, Fromholt SE, Fu C, Yachnis AT, Golde TE, Borchelt DR (2015) Murine Aβ over-production produces diffuse and compact Alzheimer-type amyloid deposits. Acta Neuropathol Commun 3:72. doi:10.1186/s40478-015-0252-9
Yagi T, Ito D, Okada Y, Akamatsu W, Nihei Y, Yoshizaki T, Yamanaka S, Okano H, Suzuki N (2011) Modeling familial Alzheimer’s disease with induced pluripotent stem cells. Hum Mol Genet 20:4530–4539. doi:10.1093/hmg/ddr394
Yamazaki Y, Painter MM, Bu G, Kanekiyo T (2016) Apolipoprotein E as a therapeutic target in Alzheimer’s disease: a review of basic research and clinical evidence. CNS Drugs 30:773–789. doi:10.1007/s40263-016-0361-4
Yoshiyama Y, Higuchi M, Zhang B, Huang SM, Iwata N, Saido TC, Maeda J, Suhara T, Trojanowski JQ, Lee VM (2007) Synapse loss and microglial activation precede tangles in a P301S tauopathy mouse model. Neuron 53:337–351
Youmans KL, Tai LM, Nwabuisi-Heath E, Jungbauer L, Kanekiyo T, Gan M, Kim J, Eimer WA, Estus S, Rebeck GW et al (2012) APOE4-specific changes in Abeta accumulation in a new transgenic mouse model of Alzheimer disease. J Biol Chem 287:41774–41786. doi:10.1074/jbc.M112.407957
Zhang-Nunes SX, Maat-Schieman ML, Van Duinen SG, Roos RA, Frosch MP, Greenberg SM (2006) The cerebral beta-amyloid angiopathies: hereditary and sporadic. Brain Pathol 16:30–39
Acknowledgements
This manuscript was supported by NIH Grants: NS073502 and AG08051. We thank Geoffrey Pires for his assistance with figure preparation.
Author information
Authors and Affiliations
Corresponding author
Electronic supplementary material
Below is the link to the electronic supplementary material.
Rights and permissions
About this article
Cite this article
Drummond, E., Wisniewski, T. Alzheimer’s disease: experimental models and reality. Acta Neuropathol 133, 155–175 (2017). https://doi.org/10.1007/s00401-016-1662-x
Received:
Revised:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00401-016-1662-x