Review Article | Published:

Rodent models for Alzheimer disease


Animal models are indispensable tools for Alzheimer disease (AD) research. Over the course of more than two decades, an increasing number of complementary rodent models has been generated. These models have facilitated testing hypotheses about the aetiology and progression of AD, dissecting the associated pathomechanisms and validating therapeutic interventions, thereby providing guidance for the design of human clinical trials. However, the lack of success in translating rodent data into therapeutic outcomes may challenge the validity of the current models. This Review critically evaluates the genetic and non-genetic strategies used in AD modelling, discussing their strengths and limitations, as well as new opportunities for the development of better models for the disease.

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  1. 1.

    World Health Organization. The epidemiology and impact of dementia. WHO (2015).

  2. 2.

    Mattace-Raso, F. Is memantine + acetylcholinesterase inhibitor treatment superior to either therapy alone in Alzheimer’s disease? J. Alzheimers Dis. 41, 641–642 (2014).

  3. 3.

    Polanco, J. C. et al. Amyloid-beta and tau complexity - towards improved biomarkers and targeted therapies. Nat. Rev. Neurol. 14, 22–39 (2018).

  4. 4.

    Goedert, M. Neurodegeneration. Alzheimer’s and Parkinson’s diseases: the prion concept in relation to assembled Abeta, tau, and alpha-synuclein. Science 349, 1255555 (2015).

  5. 5.

    Goedert, M., Spillantini, M. G., Jakes, R., Rutherford, D. & Crowther, R. A. Multiple isoforms of human microtubule-associated protein tau: sequences and localization in neurofibrillary tangles of Alzheimer’s disease. Neuron 3, 519–526 (1989).

  6. 6.

    Glenner, G. G. & Wong, C. W. Alzheimer’s disease: initial report of the purification and characterization of a novel cerebrovascular amyloid protein. Biochem. Biophys. Res. Commun. 120, 885–890 (1984).

  7. 7.

    Masters, C. L. et al. Amyloid plaque core protein in Alzheimer disease and Down syndrome. Proc. Natl Acad. Sci. USA 82, 4245–4249 (1985).

  8. 8.

    Cooper, P. N., Jackson, M., Lennox, G., Lowe, J. & Mann, D. M. Tau, ubiquitin, and alpha B-crystallin immunohistochemistry define the principal causes of degenerative frontotemporal dementia. Arch. Neurol. 52, 1011–1015 (1995).

  9. 9.

    Delacourte, A. et al. Specific pathological Tau protein variants characterize Pick’s disease. J. Neuropathol. Exp. Neurol. 55, 159–168 (1996).

  10. 10.

    Duyckaerts, C., Delatour, B. & Potier, M. C. Classification and basic pathology of Alzheimer disease. Acta Neuropathol. 118, 5–36 (2009).

  11. 11.

    Braak, H., Thal, D. R., Ghebremedhin, E. & Del Tredici, K. Stages of the pathologic process in Alzheimer disease: age categories from 1 to 100 years. J. Neuropathol. Exp. Neurol. 70, 960–969 (2011).

  12. 12.

    Cacace, R., Sleegers, K. & Van Broeckhoven, C. Molecular genetics of early-onset Alzheimer’s disease revisited. Alzheimers Dement 12, 733–748 (2016).

  13. 13.

    Verheijen, J. & Sleegers, K. Understanding Alzheimer disease at the interface between genetics and transcriptomics. Trends Genet. 34, 434–447 (2018).

  14. 14.

    Corder, E. H. et al. Gene dose of apolipoprotein E type 4 allele and the risk of Alzheimer’s disease in late onset families. Science 261, 921–923 (1993).

  15. 15.

    Harold, D. et al. Genome-wide association study identifies variants at CLU and PICALM associated with Alzheimer’s disease. Nat. Genet. 41, 1088–1093 (2009).

  16. 16.

    Guerreiro, R. et al. TREM2 variants in Alzheimer’s disease. N. Engl. J. Med. 368, 117–127 (2013).

  17. 17.

    Jonsson, T. et al. Variant of TREM2 associated with the risk of Alzheimer’s disease. N. Engl. J. Med. 368, 107–116 (2013).

  18. 18.

    Li, C. & Götz, J. Tau-based therapies in neurodegeneration – opportunities and challenges. Nat. Rev. Drug Discov. 16, 863–883 (2017).

  19. 19.

    Sasaguri, H. et al. APP mouse models for Alzheimer’s disease preclinical studies. EMBO J. 36, 2473–2487 (2017).

  20. 20.

    Dujardin, S., Colin, M. & Buée, L. Invited review: animal models of tauopathies and their implications for research/translation into the clinic. Neuropathol. Appl. Neurobiol. 41, 59–80 (2015).

  21. 21.

    Brier, M. R. et al. Tau and Abeta imaging, CSF measures, and cognition in Alzheimer’s disease. Sci. Transl Med. 8, 338ra366 (2016).

  22. 22.

    Götz, J. & Ittner, L. M. Animal models of Alzheimer’s disease and frontotemporal dementia. Nat. Rev. Neurosci. 9, 532–544 (2008).

  23. 23.

    Handley, R. R. et al. Metabolic disruption identified in the Huntington’s disease transgenic sheep model. Sci. Rep. 6, 20681 (2016).

  24. 24.

    Yan, S. et al. A Huntingtin knockin pig model recapitulates features of selective neurodegeneration in Huntington’s disease. Cell 173, 989–1002 (2018).

  25. 25.

    Lee, S. E. et al. Production of transgenic pig as an Alzheimer’s disease model using a multi-cistronic vector system. PLOS One 12, e0177933 (2017).

  26. 26.

    Gunn-Moore, D., Kaidanovich-Beilin, O., Gallego Iradi, M. C., Gunn-Moore, F. & Lovestone, S. Alzheimer’s disease in humans and other animals: a consequence of postreproductive life span and longevity rather than aging. Alzheimers Dement. 14, 195–204 (2018).

  27. 27.

    Van Dam, D. & De Deyn, P. P. Non human primate models for Alzheimer’s disease-related research and drug discovery. Expert Opin. Drug Discov. 12, 187–200 (2017).

  28. 28.

    Bateman, R. J. et al. Clinical and biomarker changes in dominantly inherited Alzheimer’s disease. N. Engl. J. Med. 367, 795–804 (2012).

  29. 29.

    Games, D. et al. Alzheimer-type neuropathology in transgenic mice overexpressing V717F beta-amyloid precursor protein. Nature 373, 523–527 (1995).

  30. 30.

    Sturchler-Pierrat, C. et al. Two amyloid precursor protein transgenic mouse models with Alzheimer disease-like pathology. Proc. Natl Acad. Sci. USA 94, 13287–13292 (1997).

  31. 31.

    Xu, G. et al. Murine Abeta over-production produces diffuse and compact Alzheimer-type amyloid deposits. Acta Neuropathol. Commun. 3, 72 (2015).

  32. 32.

    Lewis, J. et al. Neurofibrillary tangles, amyotrophy and progressive motor disturbance in mice expressing mutant (P301L) tau protein. Nat. Genet. 25, 402–405 (2000).

  33. 33.

    Götz, J. et al. Somatodendritic localization and hyperphosphorylation of tau protein in transgenic mice expressing the longest human brain tau isoform. EMBO J. 14, 1304–1313 (1995).

  34. 34.

    Allen, B. et al. Abundant tau filaments and nonapoptotic neurodegeneration in transgenic mice expressing human P301S tau protein. J. Neurosci. 22, 9340–9351 (2002).

  35. 35.

    Santacruz, K. et al. Tau suppression in a neurodegenerative mouse model improves memory function. Science 309, 476–481 (2005).

  36. 36.

    Jankowsky, J. L. et al. Co-expression of multiple transgenes in mouse CNS: a comparison of strategies. Biomol. Eng. 17, 157–165 (2001).

  37. 37.

    Oakley, H. et al. 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 (2006).

  38. 38.

    Saito, T., Matsuba, Y., Yamazaki, N., Hashimoto, S. & Saido, T. C. Calpain activation in Alzheimer’s model mice is an artifact of APP and Presenilin overexpression. J. Neurosci. 36, 9933–9936 (2016).

  39. 39.

    McGowan, E. et al. Abeta42 is essential for parenchymal and vascular amyloid deposition in mice. Neuron 47, 191–199 (2005).

  40. 40.

    Zheng, H. et al. Beta-amyloid precursor protein-deficient mice show reactive gliosis and decreased locomotor activity. Cell 81, 525–531 (1995).

  41. 41.

    Harada, A. et al. Altered microtubule organization in small-calibre axons of mice lacking tau protein. Nature 369, 488–491 (1994).

  42. 42.

    Cai, H. et al. BACE1 is the major beta-secretase for generation of Abeta peptides by neurons. Nat. Neurosci. 4, 233–234 (2001).

  43. 43.

    Shen, J. et al. Skeletal and CNS defects in Presenilin-1-deficient mice. Cell 89, 629–639 (1997).

  44. 44.

    Herreman, A. et al. Presenilin 2 deficiency causes a mild pulmonary phenotype and no changes in amyloid precursor protein processing but enhances the embryonic lethal phenotype of presenilin 1 deficiency. Proc. Natl Acad. Sci. USA 96, 11872–11877 (1999).

  45. 45.

    Gilley, J. et al. Age-dependent axonal transport and locomotor changes and tau hypophosphorylation in a “P301L” tau knockin mouse. Neurobiol. Aging 33, 621 (2012).

  46. 46.

    Saito, T. et al. Single App knock-in mouse models of Alzheimer’s disease. Nat. Neurosci. 17, 661–663 (2014). This study describes the generation and analysis of mouse models with a humanized Aβ sequence, with and without mutations in APP.

  47. 47.

    Reaume, A. G. et al. Enhanced amyloidogenic processing of the beta-amyloid precursor protein in gene-targeted mice bearing the Swedish familial Alzheimer’s disease mutations and a “humanized” Abeta sequence. J. Biol. Chem. 271, 23380–23388 (1996).

  48. 48.

    Köhler, C., Ebert, U., Baumann, K. & Schröder, H. Alzheimer’s disease-like neuropathology of gene-targeted APP-SLxPS1mut mice expressing the amyloid precursor protein at endogenous levels. Neurobiol. Dis. 20, 528–540 (2005).

  49. 49.

    Li, H. et al. Vascular and parenchymal amyloid pathology in an Alzheimer disease knock-in mouse model: interplay with cerebral blood flow. Mol. Neurodegener. 9, 28 (2014).

  50. 50.

    Masuda, A. et al. Cognitive deficits in single App knock-in mouse models. Neurobiol. Learn. Mem. 135, 73–82 (2016).

  51. 51.

    Guo, Q. et al. Increased vulnerability of hippocampal neurons to excitotoxic necrosis in presenilin-1 mutant knock-in mice. Nat. Med. 5, 101–106 (1999).

  52. 52.

    Hamanaka, H. et al. Altered cholesterol metabolism in human apolipoprotein E4 knock-in mice. Hum. Mol. Genet. 9, 353–361 (2000).

  53. 53.

    Mann, K. M. et al. Independent effects of APOE on cholesterol metabolism and brain Abeta levels in an Alzheimer disease mouse model. Hum. Mol. Genet. 13, 1959–1968 (2004).

  54. 54.

    Xia, D., Gutmann, J. M. & Götz, J. Mobility and subcellular localization of endogenous, gene-edited Tau differs from that of over-expressed human wild-type and P301L mutant Tau. Sci. Rep. 6, 29074 (2016). This study uses TALEN-based gene-editing technology to visualize endogenous tau molecules by super-resolution microscopy.

  55. 55.

    Oddo, S. et al. Triple-transgenic model of Alzheimer’s disease with plaques and tangles. Intracellular abeta and synaptic dysfunction. Neuron 39, 409–421 (2003).

  56. 56.

    LaFerla, F. M. & Green, K. N. Animal models of Alzheimer disease. Cold Spring Harb. Perspect. Med. 2, a006320 (2012).

  57. 57.

    Andorfer, C. et al. Hyperphosphorylation and aggregation of tau in mice expressing normal human tau isoforms. J. Neurochem. 86, 582–590 (2003).

  58. 58.

    Adalbert, R. et al. Interaction between a MAPT variant causing frontotemporal dementia and mutant APP affects axonal transport. Neurobiol. Aging 68, 68–75 (2018).

  59. 59.

    Takemura, M. et al. Beta/A4 proteinlike immunoreactive granular structures in the brain of senescence-accelerated mouse. Am. J. Pathol. 142, 1887–1897 (1993).

  60. 60.

    Canudas, A. M. et al. Hyperphosphorylation of microtubule-associated protein tau in senescence-accelerated mouse (SAM). Mech. Ageing Dev. 126, 1300–1304 (2005).

  61. 61.

    Delerue, F. et al. Single nucleotide variants (SNVs) define senescence-accelerated SAMP8 mice, a model of a geriatric condition. J. Alzheimers Dis. 36, 349–363 (2013).

  62. 62.

    Porquet, D. et al. Amyloid and tau pathology of familial Alzheimer’s disease APP/PS1 mouse model in a senescence phenotype background (SAMP8). Age 37, 9747 (2015).

  63. 63.

    Bodea, L. G. et al. Accelerated aging exacerbates a pre-existing pathology in a tau transgenic mouse model. Aging Cell 16, 377–386 (2017).

  64. 64.

    Virgili, J. et al. Characterization of a 3 × Tg-AD mouse model of Alzheimer’s disease with the senescence accelerated mouse prone 8 (SAMP8) background. Synapse 72, e22025 (2018).

  65. 65.

    Götz, J., Chen, F., van Dorpe, J. & Nitsch, R. M. Formation of neurofibrillary tangles in P301L tau transgenic mice induced by Abeta 42 fibrils. Science 293, 1491–1495 (2001).

  66. 66.

    Bolmont, T. et al. Induction of tau pathology by intracerebral infusion of amyloid-beta -containing brain extract and by amyloid-beta deposition in APP x Tau transgenic mice. Am. J. Pathol. 171, 2012–2020 (2007).

  67. 67.

    Clavaguera, F. et al. Transmission and spreading of tauopathy in transgenic mouse brain. Nat. Cell Biol. 11, 909–913 (2009). This study reveals the seeding and spreading capacities of exogenous tau in a mouse model for AD.

  68. 68.

    He, Z. et al. Amyloid-beta plaques enhance Alzheimer’s brain tau-seeded pathologies by facilitating neuritic plaque tau aggregation. Nat. Med. 24, 29–38 (2018).

  69. 69.

    Chu, J., Giannopoulos, P. F., Ceballos-Diaz, C., Golde, T. E. & Pratico, D. Adeno-associated virus-mediated brain delivery of 5-lipoxygenase modulates the AD-like phenotype of APP mice. Mol. Neurodegener. 7, 1 (2012).

  70. 70.

    Yu, F., Zhang, Y. & Chuang, D. M. Lithium reduces BACE1 overexpression, beta amyloid accumulation, and spatial learning deficits in mice with traumatic brain injury. J. Neurotrauma 29, 2342–2351 (2012).

  71. 71.

    Ojo, J. O. et al. Repetitive mild traumatic brain injury augments tau pathology and glial activation in aged hTau mice. J. Neuropathol. Exp. Neurol. 72, 137–151 (2013).

  72. 72.

    Tran, H. T., LaFerla, F. M., Holtzman, D. M. & Brody, D. L. Controlled cortical impact traumatic brain injury in 3xTg-AD mice causes acute intra-axonal amyloid-beta accumulation and independently accelerates the development of tau abnormalities. J. Neurosci. 31, 9513–9525 (2011).

  73. 73.

    Eisele, Y. S. et al. Peripherally applied Abeta-containing inoculates induce cerebral beta-amyloidosis. Science 330, 980–982 (2010). This study shows that cerebral β-amyloidosis can be seeded by protein aggregates delivered into the peritoneal cavity, reminiscent of prion disease.

  74. 74.

    Clavaguera, F. et al. Peripheral administration of tau aggregates triggers intracerebral tauopathy in transgenic mice. Acta Neuropathol. 127, 299–301 (2014).

  75. 75.

    Baker, S. & Götz, J. A local insult of okadaic acid in wild-type mice induces tau phosphorylation and protein aggregation in anatomically distinct brain regions. Acta Neuropathol. Commun. 4, 32 (2016).

  76. 76.

    Krstic, D. et al. Systemic immune challenges trigger and drive Alzheimer-like neuropathology in mice. J. Neuroinflamm. 9, 151 (2012).

  77. 77.

    Gallardo, G. & Holtzman, D. M. Antibody therapeutics targeting Abeta and Tau. Cold Spring Harb. Perspect. Med. 7, a024331 (2017).

  78. 78.

    DeVos, S. L. et al. Tau reduction prevents neuronal loss and reverses pathological tau deposition and seeding in mice with tauopathy. Sci. Transl Med. 9, eaag0481 (2017). This study uses antisense oligonucleotides to decrease levels of tau transcripts in an AD mouse model, leading to the amelioration of pathology.

  79. 79.

    Xu, H. et al. Tau silencing by siRNA in the P301S mouse model of tauopathy. Curr. Gene Ther. 14, 343–351 (2014).

  80. 80.

    Espindola, S. L. et al. Modulation of Tau isoforms imbalance precludes Tau pathology and cognitive decline in a mouse model of tauopathy. Cell Rep. 23, 709–715 (2018).

  81. 81.

    Kummer, M. P. & Heneka, M. T. Truncated and modified amyloid-beta species. Alzheimers Res. Ther. 6, 28 (2014).

  82. 82.

    Morris, M. et al. Tau post-translational modifications in wild-type and human amyloid precursor protein transgenic mice. Nat. Neurosci. 18, 1183–1189 (2015). This proteomics study reveals the complexity of tau’s post-translational modifications even under normal conditions.

  83. 83.

    Tracy, T. E. et al. Acetylated Tau obstructs KIBRA-mediated signaling in synaptic plasticity and promotes tauopathy-related memory loss. Neuron 90, 245–260 (2016).

  84. 84.

    Ozcelik, S. et al. Co-expression of truncated and full-length tau induces severe neurotoxicity. Mol. Psychiatry 21, 1790–1798 (2016).

  85. 85.

    Alexandru, A. et al. Selective hippocampal neurodegeneration in transgenic mice expressing small amounts of truncated Abeta is induced by pyroglutamate-Abeta formation. J. Neurosci. 31, 12790–12801 (2011).

  86. 86.

    Ittner, L. M. et al. Dendritic function of tau mediates amyloid-beta toxicity in Alzheimer’s disease mouse models. Cell 142, 387–397 (2010).

  87. 87.

    Li, X. et al. Novel diffusion barrier for axonal retention of Tau in neurons and its failure in neurodegeneration. EMBO J. 30, 4825–4837 (2011).

  88. 88.

    Li, C. & Götz, J. Somatodendritic accumulation of Tau in Alzheimer’s disease is promoted by Fyn-mediated local protein translation. EMBO J. 36, 3120–3138 (2017). This study proposes an alternative mechanism for the pathological accumulation of tau in the somatodendritic domain, involving de novo protein synthesis mediated by the FYN–ERK–RPS6 cascade.

  89. 89.

    Cochran, J. N. et al. AlphaScreen HTS and live-cell bioluminescence resonance energy transfer (BRET) assays for identification of Tau-Fyn SH3 interaction inhibitors for Alzheimer disease. J. Biomol. Screen. 19, 1338–1349 (2014).

  90. 90.

    Um, J. W. et al. Alzheimer amyloid-beta oligomer bound to postsynaptic prion protein activates Fyn to impair neurons. Nat. Neurosci. 15, 1227–1235 (2012).

  91. 91.

    Salazar, S. V. et al. Conditional deletion of Prnp rescues behavioral and synaptic deficits after disease onset in transgenic Alzheimer’s disease. J. Neurosci. 37, 9207–9221 (2017).

  92. 92.

    Ittner, A. et al. Site-specific phosphorylation of tau inhibits amyloid-beta toxicity in Alzheimer’s mice. Science 354, 904–908 (2016). This study uses AD mouse models to reveal a protective function associated with a distinct tau phosphorylation event.

  93. 93.

    Boehm, J. A ‘danse macabre’: tau and Fyn in STEP with amyloid beta to facilitate induction of synaptic depression and excitotoxicity. Eur. J. Neurosci. 37, 1925–1930 (2013).

  94. 94.

    Roberson, E. D. et al. Reducing endogenous tau ameliorates amyloid beta-induced deficits in an Alzheimer’s disease mouse model. Science 316, 750–754 (2007). This study identifies an essential role for tau in mediating Aβ toxicity.

  95. 95.

    DeVos, S. L. et al. Antisense reduction of tau in adult mice protects against seizures. J. Neurosci. 33, 12887–12897 (2013).

  96. 96.

    Hatch, R. J., Wei, Y., Xia, D. & Götz, J. Hyperphosphorylated tau causes reduced hippocampal CA1 excitability by relocating the axon initial segment. Acta Neuropathol. 133, 717–730 (2017).

  97. 97.

    Marin, M. A., Ziburkus, J., Jankowsky, J. & Rasband, M. N. Amyloid-beta plaques disrupt axon initial segments. Exp. Neurol. 281, 93–98 (2016).

  98. 98.

    Bereczki, E. et al. Synaptic markers of cognitive decline in neurodegenerative diseases: a proteomic approach. Brain 141, 582–595 (2018).

  99. 99.

    Tackenberg, C. & Brandt, R. Divergent pathways mediate spine alterations and cell death induced by amyloid-beta, wild-type tau, and R406W tau. J. Neurosci. 29, 14439–14450 (2009).

  100. 100.

    Serrano-Pozo, A., Frosch, M. P., Masliah, E. & Hyman, B. T. Neuropathological alterations in Alzheimer disease. Cold Spring Harb. Perspect. Med. 1, a006189 (2011).

  101. 101.

    Arbel-Ornath, M. et al. Soluble oligomeric amyloid-beta induces calcium dyshomeostasis that precedes synapse loss in the living mouse brain. Mol. Neurodegener. 12, 27 (2017).

  102. 102.

    Arendt, T. Synaptic degeneration in Alzheimer’s disease. Acta Neuropathol. 118, 167–179 (2009).

  103. 103.

    Xia, D. et al. Presenilin-1 knockin mice reveal loss-of-function mechanism for familial Alzheimer’s disease. Neuron 85, 967–981 (2015).

  104. 104.

    Donoviel, D. B. et al. Mice lacking both presenilin genes exhibit early embryonic patterning defects. Genes Dev. 13, 2801–2810 (1999).

  105. 105.

    Saura, C. A. et al. Loss of presenilin function causes impairments of memory and synaptic plasticity followed by age-dependent neurodegeneration. Neuron 42, 23–36 (2004).

  106. 106.

    Feng, R. et al. Forebrain degeneration and ventricle enlargement caused by double knockout of Alzheimer’s presenilin-1 and presenilin-2. Proc. Natl Acad. Sci. USA 101, 8162–8167 (2004).

  107. 107.

    Wines-Samuelson, M. et al. Characterization of age-dependent and progressive cortical neuronal degeneration in presenilin conditional mutant mice. PLOS One 5, e10195 (2010).

  108. 108.

    Wang, B. et al. Gamma-secretase gene mutations in familial acne inversa. Science 330, 1065 (2010).

  109. 109.

    Shen, J. & Kelleher, R. J. III. The presenilin hypothesis of Alzheimer’s disease: evidence for a loss-of-function pathogenic mechanism. Proc. Natl Acad. Sci. USA 104, 403–409 (2007).

  110. 110.

    Kretner, B. et al. Generation and deposition of Abeta43 by the virtually inactive presenilin-1 L435F mutant contradicts the presenilin loss-of-function hypothesis of Alzheimer’s disease. EMBO Mol. Med. 8, 458–465 (2016).

  111. 111.

    Maeda, S. et al. Expression of A152T human tau causes age-dependent neuronal dysfunction and loss in transgenic mice. EMBO Rep. 17, 530–551 (2016).

  112. 112.

    Palop, J. J., Chin, J. & Mucke, L. A network dysfunction perspective on neurodegenerative diseases. Nature 443, 768–773 (2006).

  113. 113.

    Greicius, M. D., Srivastava, G., Reiss, A. L. & Menon, V. Default-mode network activity distinguishes Alzheimer’s disease from healthy aging: evidence from functional MRI. Proc. Natl Acad. Sci. USA 101, 4637–4642 (2004).

  114. 114.

    Sperling, R. A. et al. Amyloid deposition is associated with impaired default network function in older persons without dementia. Neuron 63, 178–188 (2009).

  115. 115.

    Palop, J. J. et al. Aberrant excitatory neuronal activity and compensatory remodeling of inhibitory hippocampal circuits in mouse models of Alzheimer’s disease. Neuron 55, 697–711 (2007). This study in AD mouse models identifies a role for aberrant network activity triggered by Aβ-mediated overexcitation.

  116. 116.

    Kuchibhotla, K. V., Lattarulo, C. R., Hyman, B. T. & Bacskai, B. J. Synchronous hyperactivity and intercellular calcium waves in astrocytes in Alzheimer mice. Science 323, 1211–1215 (2009).

  117. 117.

    Siskova, Z. et al. Dendritic structural degeneration is functionally linked to cellular hyperexcitability in a mouse model of Alzheimer’s disease. Neuron 84, 1023–1033 (2014).

  118. 118.

    Hall, A. M. et al. Tau-dependent Kv4.2 depletion and dendritic hyperexcitability in a mouse model of Alzheimer’s disease. J. Neurosci. 35, 6221–6230 (2015).

  119. 119.

    Harris, J. A. et al. Transsynaptic progression of amyloid-beta-induced neuronal dysfunction within the entorhinal-hippocampal network. Neuron 68, 428–441 (2010).

  120. 120.

    Fu, H. et al. Tau pathology induces excitatory neuron loss, grid cell dysfunction, and spatial memory deficits reminiscent of early Alzheimer’s disease. Neuron 93, 533–541.e5 (2017).

  121. 121.

    Stancu, I. C. et al. Templated misfolding of Tau by prion-like seeding along neuronal connections impairs neuronal network function and associated behavioral outcomes in Tau transgenic mice. Acta Neuropathol. 129, 875–894 (2015).

  122. 122.

    Guo, J. L. et al. Unique pathological tau conformers from Alzheimer’s brains transmit tau pathology in nontransgenic mice. J. Exp. Med. 213, 2635–2654 (2016).

  123. 123.

    Braak, H. & Braak, E. Staging of Alzheimer’s disease-related neurofibrillary changes. Neurobiol. Aging 16, 271–284 (1995).

  124. 124.

    Calafate, S. et al. Synaptic contacts enhance cell-to-cell Tau pathology propagation. Cell Rep. 11, 1176–1183 (2015).

  125. 125.

    Sanders, D. W. et al. Distinct tau prion strains propagate in cells and mice and define different tauopathies. Neuron 82, 1271–1288 (2014).

  126. 126.

    Polanco, J. C., Scicluna, B. J., Hill, A. F. & Götz, J. Extracellular vesicles isolated from the brains of rTg4510 mice seed Tau protein aggregation in a threshold-dependent manner. J. Biol. Chem. 291, 12445–12466 (2016).

  127. 127.

    Chung, W. S. et al. Novel allele-dependent role for APOE in controlling the rate of synapse pruning by astrocytes. Proc. Natl Acad. Sci. USA 113, 10186–10191 (2016).

  128. 128.

    Takahashi, K., Rochford, C. D. & Neumann, H. Clearance of apoptotic neurons without inflammation by microglial triggering receptor expressed on myeloid cells-2. J. Exp. Med. 201, 647–657 (2005).

  129. 129.

    Azevedo, F. A. et al. Equal numbers of neuronal and nonneuronal cells make the human brain an isometrically scaled-up primate brain. J. Comp. Neurol. 513, 532–541 (2009).

  130. 130.

    Gomez-Nicola, D. & Perry, V. H. Microglial dynamics and role in the healthy and diseased brain: a paradigm of functional plasticity. Neuroscientist 21, 169–184 (2015).

  131. 131.

    Hong, S. et al. Complement and microglia mediate early synapse loss in Alzheimer mouse models. Science 352, 712–716 (2016). This study suggests a role for the aberrant activation of the complement cascade and microglia in the elimination of synapses in a process similar to that of synaptic pruning in development.

  132. 132.

    Gjoneska, E. et al. Conserved epigenomic signals in mice and humans reveal immune basis of Alzheimer’s disease. Nature 518, 365–369 (2015).

  133. 133.

    Zhang, B. et al. Integrated systems approach identifies genetic nodes and networks in late-onset Alzheimer’s disease. Cell 153, 707–720 (2013).

  134. 134.

    Meyer-Luehmann, M. & Prinz, M. Myeloid cells in Alzheimer’s disease: culprits, victims or innocent bystanders? Trends Neurosci. 38, 659–668 (2015).

  135. 135.

    Grathwohl, S. A. et al. Formation and maintenance of Alzheimer’s disease beta-amyloid plaques in the absence of microglia. Nat. Neurosci. 12, 1361–1363 (2009).

  136. 136.

    Spangenberg, E. E. et al. Eliminating microglia in Alzheimer’s mice prevents neuronal loss without modulating amyloid-beta pathology. Brain 139, 1265–1281 (2016).

  137. 137.

    Sarlus, H. & Heneka, M. T. Microglia in Alzheimer’s disease. J. Clin. Invest. 127, 3240–3249 (2017).

  138. 138.

    Daria, A. et al. Young microglia restore amyloid plaque clearance of aged microglia. EMBO J. 36, 583–603 (2017). This study involving co-culturing of organotypic slices taken from AD mouse models and wild-type mice suggests that microglial function can be modulated to the extent that plaques are being cleared.

  139. 139.

    Lei, P. et al. Tau deficiency induces parkinsonism with dementia by impairing APP-mediated iron export. Nat. Med. 18, 291–295 (2012).

  140. 140.

    Wendeln, A. C. et al. Innate immune memory in the brain shapes neurological disease hallmarks. Nature 556, 332–338 (2018).

  141. 141.

    Scholtzova, H. et al. Innate immunity stimulation via Toll-like receptor 9 ameliorates vascular amyloid pathology in Tg-SwDI mice with associated cognitive benefits. J. Neurosci. 37, 936–959 (2017).

  142. 142.

    Asai, H. et al. Depletion of microglia and inhibition of exosome synthesis halt tau propagation. Nat. Neurosci. 18, 1584–1593 (2015). This study proposes an exosome-mediated tau seeding mechanism involving microglia.

  143. 143.

    Bhaskar, K. et al. Regulation of tau pathology by the microglial fractalkine receptor. Neuron 68, 19–31 (2010).

  144. 144.

    Lee, S. et al. Opposing effects of membrane-anchored CX3CL1 on amyloid and tau pathologies via the p38 MAPK pathway. J. Neurosci. 34, 12538–12546 (2014).

  145. 145.

    Jiang, T. et al. Silencing of TREM2 exacerbates tau pathology, neurodegenerative changes, and spatial learning deficits in P301S tau transgenic mice. Neurobiol. Aging 36, 3176–3186 (2015).

  146. 146.

    Leyns, C. E. G. et al. TREM2 deficiency attenuates neuroinflammation and protects against neurodegeneration in a mouse model of tauopathy. Proc. Natl Acad. Sci. USA 114, 11524–11529 (2017).

  147. 147.

    Keren-Shaul, H. et al. A unique microglia type associated with restricting development of Alzheimer’s disease. Cell 169, 1276–1290 (2017).

  148. 148.

    Yuan, P. et al. TREM2 haplodeficiency in mice and humans impairs the microglia barrier function leading to decreased amyloid compaction and severe axonal dystrophy. Neuron 90, 724–739 (2016). This study reveals a TREM2-dependent involvement of microglia in the compaction of amyloid plaques.

  149. 149.

    Kleinberger, G. et al. TREM2 mutations implicated in neurodegeneration impair cell surface transport and phagocytosis. Sci. Transl Med. 6, 243ra286 (2014).

  150. 150.

    Song, W. M. et al. Humanized TREM2 mice reveal microglia-intrinsic and -extrinsic effects of R47H polymorphism. J. Exp. Med. 215, 745–760 (2018).

  151. 151.

    Lambert, J. C. et al. Genome-wide association study identifies variants at CLU and CR1 associated with Alzheimer’s disease. Nat. Genet. 41, 1094–1099 (2009).

  152. 152.

    Krasemann, S. et al. The TREM2-APOE pathway drives the transcriptional phenotype of dysfunctional microglia in neurodegenerative diseases. Immunity 47, 566–581 (2017).

  153. 153.

    Ittner, L. M. et al. Parkinsonism and impaired axonal transport in a mouse model of frontotemporal dementia. Proc. Natl Acad. Sci. USA 105, 15997–16002 (2008).

  154. 154.

    Taft, R. A., Davisson, M. & Wiles, M. V. Know thy mouse. Trends Genet. 22, 649–653 (2006).

  155. 155.

    Srivastava, A. et al. Genomes of the Mouse Collaborative Cross. Genetics 206, 537–556 (2017).

  156. 156.

    Rasmussen, J. et al. Amyloid polymorphisms constitute distinct clouds of conformational variants in different etiological subtypes of Alzheimer’s disease. Proc. Natl Acad. Sci. USA 114, 13018–13023 (2017). This study uses a novel class of amyloid dyes revealing conformational variants potentially linked to the different subtypes of AD.

  157. 157.

    Fitzpatrick, A. W. P. et al. Cryo-EM structures of tau filaments from Alzheimer’s disease. Nature 547, 185–190 (2017). This study shows that paired and straight tau filaments in AD are each composed of two identical protofilaments that differ in their inter-protofilament packing.

  158. 158.

    Vigouroux, R. J., Belle, M. & Chedotal, A. Neuroscience in the third dimension: shedding new light on the brain with tissue clearing. Mol. Brain 10, 33 (2017).

  159. 159.

    Kuhla, A. et al. APPswe/PS1dE9 mice with cortical amyloid pathology show a reduced NAA/Cr ratio without apparent brain atrophy: a MRS and MRI study. Neuroimage Clin. 15, 581–586 (2017).

  160. 160.

    Eggel, A. & Wyss-Coray, T. A revival of parabiosis in biomedical research. Swiss Med. Wkly 144, w13914 (2014).

  161. 161.

    Villeda, S. A. et al. Young blood reverses age-related impairments in cognitive function and synaptic plasticity in mice. Nat. Med. 20, 659–663 (2014).

  162. 162.

    Middeldorp, J. et al. Preclinical assessment of young blood plasma for Alzheimer disease. JAMA Neurol. 73, 1325–1333 (2016).

  163. 163.

    Roy, D. S. et al. Memory retrieval by activating engram cells in mouse models of early Alzheimer’s disease. Nature 531, 508–512 (2016). The optogenetic activation of hippocampal memory engram cells in AD mouse models suggests a retrieval, rather than a storage, impairment at an early stage of AD.

  164. 164.

    Cirrito, J. R. et al. Endocytosis is required for synaptic activity-dependent release of amyloid-beta in vivo. Neuron 58, 42–51 (2008).

  165. 165.

    Yamamoto, K. et al. Chronic optogenetic activation augments abeta pathology in a mouse model of Alzheimer disease. Cell Rep. 11, 859–865 (2015).

  166. 166.

    Noetzli, M. & Eap, C. B. Pharmacodynamic, pharmacokinetic and pharmacogenetic aspects of drugs used in the treatment of Alzheimer’s disease. Clin. Pharmacokinet. 52, 225–241 (2013).

  167. 167.

    Pilotto, A. et al. Effect of a CYP2D6 polymorphism on the efficacy of donepezil in patients with Alzheimer disease. Neurology 73, 761–767 (2009).

  168. 168.

    Seripa, D. et al. Role of cytochrome P4502D6 functional polymorphisms in the efficacy of donepezil in patients with Alzheimer’s disease. Pharmacogenet. Genomics 21, 225–230 (2011).

  169. 169.

    Matarin, M. et al. A genome-wide gene-expression analysis and database in transgenic mice during development of amyloid or tau pathology. Cell Rep. 10, 633–644 (2015). This detailed study in several AD mouse models reveals that amyloid build-up correlates with the expression of immune genes, whereas tau pathology correlates negatively with the expression of synaptic genes.

  170. 170.

    Gaiteri, C., Mostafavi, S., Honey, C. J., De Jager, P. L. & Bennett, D. A. Genetic variants in Alzheimer disease - molecular and brain network approaches. Nat. Rev. Neurol. 12, 413–427 (2016).

  171. 171.

    Necula, M., Kayed, R., Milton, S. & Glabe, C. G. Small molecule inhibitors of aggregation indicate that amyloid beta oligomerization and fibrillization pathways are independent and distinct. J. Biol. Chem. 282, 10311–10324 (2007).

  172. 172.

    Liu, P. et al. Quaternary structure defines a large class of amyloid-β oligomers neutralized by sequestration. Cell Rep. 11, 1760–1771 (2015).

  173. 173.

    Iijima, K. et al. Dissecting the pathological effects of human Aβ40 and Aβ42 in Drosophila: a potential model for Alzheimer’s disease. Proc. Natl Acad. Sci. USA 101, 6623–6628 (2004).

  174. 174.

    Duran-Aniotz, C., Morales, R., Moreno-Gonzalez, I., Hu, P. P. & Soto, C. Brains from non-Alzheimer’s individuals containing amyloid deposits accelerate Aβ deposition in vivo. Acta Neuropathol. Commun. 1, 76 (2013).

  175. 175.

    Vandermeeren, M. et al. Detection of tau proteins in normal and Alzheimer’s disease cerebrospinal fluid with a sensitive sandwich enzyme-linked immunosorbent assay. J. Neurochem. 61, 1828–1834 (1993).

  176. 176.

    Maruyama, M. et al. Imaging of tau pathology in a tauopathy mouse model and in Alzheimer patients compared to normal controls. Neuron 79, 1094–1108 (2013).

  177. 177.

    Lathuilière, A. et al. Motifs in the tau protein that control binding to microtubules and aggregation determine pathological effects. Sci. Rep. 7, 13556 (2017).

  178. 178.

    Yoshida, H. & Goedert, M. Sequential phosphorylation of tau protein by cAMP-dependent protein kinase and SAPK4/p38delta or JNK2 in the presence of heparin generates the AT100 epitope. J. Neurochem 99, 154-164 (2006).

  179. 179.

    Ellenbroek, B. & Youn, J. Rodent models in neuroscience research: is it a rat race? Dis. Model. Mech. 9, 1079–1087 (2016).

  180. 180.

    Whishaw, I. Q., Metz, G. A., Kolb, B. & Pellis, S. M. Accelerated nervous system development contributes to behavioral efficiency in the laboratory mouse: a behavioral review and theoretical proposal. Dev. Psychobiol. 39, 151–170 (2001).

  181. 181.

    Lipp, H. P. & Wolfer, D. P. Genetically modified mice and cognition. Curr. Opin. Neurobiol. 8, 272–280 (1998).

  182. 182.

    Charreau, B., Tesson, L., Soulillou, J. P., Pourcel, C. & Anegon, I. Transgenesis in rats: technical aspects and models. Transgen. Res. 5, 223–234 (1996).

  183. 183.

    Echeverria, V. et al. Rat transgenic models with a phenotype of intracellular Abeta accumulation in hippocampus and cortex. J. Alzheimers Dis. 6, 209–219 (2004).

  184. 184.

    Flood, D. G. et al. A transgenic rat model of Alzheimer’s disease with extracellular Abeta deposition. Neurobiol. Aging 30, 1078–1090 (2009).

  185. 185.

    Leon, W. C. et al. A novel transgenic rat model with a full Alzheimer’s-like amyloid pathology displays pre-plaque intracellular amyloid-beta-associated cognitive impairment. J. Alzheimers Dis. 20, 113–126 (2010).

  186. 186.

    Cohen, R. M. et al. A transgenic Alzheimer rat with plaques, tau pathology, behavioral impairment, oligomeric abeta, and frank neuronal loss. J. Neurosci. 33, 6245–6256 (2013).

  187. 187.

    Zilka, N. et al. Truncated tau from sporadic Alzheimer’s disease suffices to drive neurofibrillary degeneration in vivo. FEBS Lett. 580, 3582–3588 (2006).

  188. 188.

    Filipcik, P. et al. First transgenic rat model developing progressive cortical neurofibrillary tangles. Neurobiol. Aging 33, 1448–1456 (2012).

  189. 189.

    Li, D. B. et al. Comparative study of histopathology changes between the PS1/APP double transgenic mouse model and Abeta1-40 -injected rat model of Alzheimer disease. Neurosci. Bull. 22, 52–57 (2006).

  190. 190.

    Ferretti, M. T. et al. Transgenic mice as a model of pre-clinical Alzheimer’s disease. Curr. Alzheimer Res. 8, 4–23 (2011).

  191. 191.

    Espuny-Camacho, I. et al. Hallmarks of Alzheimer’s disease in stem-cell-derived human neurons transplanted into mouse brain. Neuron 93, 1066–1081 (2017). This study shows integration of transplanted human neurons derived from induced pluripotent stem cells in a mouse brain with Aβ deposits, with neurodegeneration and neuronal loss found in human, but not murine, transplants.

  192. 192.

    Lee, I. S. et al. Human neural stem cells alleviate Alzheimer-like pathology in a mouse model. Mol. Neurodegener. 10, 38 (2015).

  193. 193.

    Marsh, S. E. et al. HuCNS-SC human NSCs Fail to differentiate, form ectopic clusters, and provide no cognitive benefits in a transgenic model of Alzheimer’s disease. Stem Cell Rep. 8, 235–248 (2017).

  194. 194.

    Choi, S. H. et al. A three-dimensional human neural cell culture model of Alzheimer’s disease. Nature 515, 274–278 (2014).

  195. 195.

    Raja, W. K. et al. Self-organizing 3D human neural tissue derived from induced pluripotent stem cells recapitulate Alzheimer’s disease phenotypes. PLOS One 11, e0161969 (2016).

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J.G. and L.-G.B. acknowledge support by the National Health and Medical Research Council of Australia (grants GNT1127999 and GNT1147569). M.G. is an Honorary Professor in the Department of Clinical Neurosciences of the University of Cambridge. This work was supported by the UK Medical Research Council (grant MC_U105184291). L.-G.B. is supported by the Peter Hilton Fellowship. The authors thank R. Tweedale for critically reading the manuscript.

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Nature Reviews Neuroscience thanks E. Roberson, J. Shen and T. Wisniewski for their contribution to the peer review of this work.

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The authors all researched data for the article, provided substantial contributions to discussion of content, wrote the article and reviewed and edited the manuscript before submission.

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The authors declare no competing interests.

Correspondence to Jürgen Götz.

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Supplementary Figure 1


Amyloid-β cascade hypothesis

Hypothesis postulating that the neurodegeneration in AD is caused by the abnormal accumulation of Aβ, which subsequently leads to tau pathology and neuronal loss.

Tau seeding

Pathological forms of tau that transfer their properties in a process of templating to non-aggregated forms of tau.

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Further reading

Fig. 1: Alignment of human and mouse forms of three key proteins implicated in Alzheimer disease.
Fig. 2: Structural differences between the three key molecules implicated in Alzheimer disease.
Fig. 3: Principal approaches in generating rodent models.