Review Article | Published:

Beyond the neuron–cellular interactions early in Alzheimer disease pathogenesis

Nature Reviews Neurosciencevolume 20pages94108 (2019) | Download Citation

Abstract

The symptoms of Alzheimer disease reflect a loss of neural circuit integrity in the brain, but neurons do not work in isolation. Emerging evidence suggests that the intricate balance of interactions between neurons, astrocytes, microglia and vascular cells required for healthy brain function becomes perturbed during the disease, with early changes likely protecting neural circuits from damage, followed later by harmful effects when the balance cannot be restored. Moving beyond a neuronal focus to understand the complex cellular interactions in Alzheimer disease and how these change throughout the course of the disease may provide important insight into developing effective therapeutics.

Access optionsAccess options

Rent or Buy article

Get time limited or full article access on ReadCube.

from$8.99

All prices are NET prices.

Additional information

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

References

  1. 1.

    World Health Organization. Dementia, a global health priority. https://www.who.int/mental_health/publications/dementia_report_2012/en/ (WHO, 2017).

  2. 2.

    De Strooper, B. & Karran, E. The cellular phase of Alzheimer’s disease. Cell 164, 603–615 (2016).

  3. 3.

    Hardy, J. A. & Higgins, G. A. Alzheimer’s disease: the amyloid cascade hypothesis. Science 256, 184–185 (1992).

  4. 4.

    Karran, E. & De Strooper, B. The amyloid cascade hypothesis: are we poised for success or failure? J. Neurochem. 139, 237–252 (2016).

  5. 5.

    Villegas-Llerena, C., Phillips, A., Garcia-Reitboeck, P., Hardy, J. & Pocock, J. M. Microglial genes regulating neuroinflammation in the progression of Alzheimer’s disease. Curr. Opin. Neurobiol. 36, 74–81 (2016).

  6. 6.

    Livingston, G. et al. Dementia prevention, intervention, and care. Lancet 390, 2673–2734 (2017).

  7. 7.

    Iadecola, C. The pathobiology of vascular dementia. Neuron 80, 844–866 (2013).

  8. 8.

    Kisler, K., Nelson, A. R., Montagne, A. & Zlokovic, B. V. Cerebral blood flow regulation and neurovascular dysfunction in Alzheimer disease. Nat. Rev. Neurosci. 18, 419–434 (2017).

  9. 9.

    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). This landmark paper identifies APOE4 as a genetic risk factor for late-onset AD.

  10. 10.

    Zlokovic, B. V. Neurovascular pathways to neurodegeneration in Alzheimer’s disease and other disorders. Nat. Rev. Neurosci. 12, 723–738 (2011).

  11. 11.

    Bennett, R. E. et al. Tau induces blood vessel abnormalities and angiogenesis-related gene expression in P301L transgenic mice and human Alzheimer’s disease. Proc. Natl Acad. Sci. USA 115, E1289–E1298 (2018).

  12. 12.

    Condello, C., Yuan, P., Schain, A. & Grutzendler, J. Microglia constitute a barrier that prevents neurotoxic protofibrillar Aβ42 hotspots around plaques. Nat. Commun. 6, 6176 (2015).

  13. 13.

    Heneka, M. T. et al. Neuroinflammation in Alzheimer’s disease. Lancet. Neurol. 14, 388–405 (2015).

  14. 14.

    Lue, L. F. et al. Involvement of microglial receptor for advanced glycation endproducts (RAGE) in Alzheimer’s disease: identification of a cellular activation mechanism. Exp. Neurol. 171, 29–45 (2001).

  15. 15.

    Zhao, R., Hu, W., Tsai, J., Li, W. & Gan, W. B. Microglia limit the expansion of beta-amyloid plaques in a mouse model of Alzheimer’s disease. Mol. Neurodegener. 12, 47 (2017).

  16. 16.

    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).

  17. 17.

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

  18. 18.

    Olmos-Alonso, A. et al. Pharmacological targeting of CSF1R inhibits microglial proliferation and prevents the progression of Alzheimer’s-like pathology. Brain 139, 891–907 (2016).

  19. 19.

    Czirr, E. et al. Microglial complement receptor 3 regulates brain Aβ levels through secreted proteolytic activity. J. Exp. Med. 214, 1081–1092 (2017).

  20. 20.

    Tay, T. L. et al. A new fate mapping system reveals context-dependent random or clonal expansion of microglia. Nat. Neurosci. 20, 793–803 (2017).

  21. 21.

    Korin, B. et al. High-dimensional, single-cell characterization of the brain’s immune compartment. Nat. Neurosci. 20, 1300–1309 (2017).

  22. 22.

    Korin, B., Dubovik, T. & Rolls, A. Mass cytometry analysis of immune cells in the brain. Nat. Protoc. 13, 377–391 (2018).

  23. 23.

    Keren-Shaul, H. et al. A unique microglia type associated with restricting development of Alzheimer’s disease. Cell 169, 1276–1290 (2017). This study uses single-cell transcriptomics to identify a subset of microglia surrounding plaques in an AD mouse model. Activation of these DAMs requires TREM2.

  24. 24.

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

  25. 25.

    Yeh, F. L., Wang, Y., Tom, I., Gonzalez, L. C. & Sheng, M. TREM2 binds to apolipoproteins, including APOE and CLU/APOJ, and thereby facilitates uptake of amyloid-beta by microglia. Neuron 91, 328–340 (2016).

  26. 26.

    Jay, T. R. et al. Disease progression-dependent effects of TREM2 deficiency in a mouse model of Alzheimer’s disease. J. Neurosci. 37, 637–647 (2017).

  27. 27.

    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).

  28. 28.

    Ulrich, J. D. et al. Altered microglial response to Aβ plaques in APPPS1-21 mice heterozygous for TREM2. Mol. Neurodegener. 9, 20 (2014).

  29. 29.

    Jay, T. R. et al. TREM2 deficiency eliminates TREM2+inflammatory macrophages and ameliorates pathology in Alzheimer’s disease mouse models. J. Exp. Med. 212, 287–295 (2015).

  30. 30.

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

  31. 31.

    Wang, Y. et al. TREM2-mediated early microglial response limits diffusion and toxicity of amyloid plaques. J. Exp. Med. 213, 667–675 (2016).

  32. 32.

    Kim, S. M. et al. TREM2 promotes Aβ phagocytosis by upregulating C/EBPα-dependent CD36 expression in microglia. Sci. Rep. 7, 11118 (2017).

  33. 33.

    Wyss-Coray, T. et al. Adult mouse astrocytes degrade amyloid-beta in vitro and in situ. Nat. Med. 9, 453–457 (2003).

  34. 34.

    Leal, M. C. et al. Plaque-associated overexpression of insulin-degrading enzyme in the cerebral cortex of aged transgenic tg2576 mice with Alzheimer pathology. J. Neuropathol. Exp. Neurol. 65, 976–987 (2006).

  35. 35.

    Deb, S., Wenjun Zhang, J. & Gottschall, P. E. Beta-amyloid induces the production of active, matrix-degrading proteases in cultured rat astrocytes. Brain Res. 970, 205–213 (2003).

  36. 36.

    Yin, K. J. et al. Matrix metalloproteinases expressed by astrocytes mediate extracellular amyloid-beta peptide catabolism. J. Neurosci. 26, 10939–10948 (2006).

  37. 37.

    Mrak, R. E., Sheng, J. G. & Griffin, W. S. Correlation of astrocytic S100 beta expression with dystrophic neurites in amyloid plaques of Alzheimer’s disease. J. Neuropathol. Exp. Neurol. 55, 273–279 (1996).

  38. 38.

    Hudry, E. et al. Gene transfer of human Apoe isoforms results in differential modulation of amyloid deposition and neurotoxicity in mouse brain. Sci. Transl Med. 5, 212ra161 (2013).

  39. 39.

    Bales, K. R. et al. Lack of apolipoprotein E dramatically reduces amyloid beta-peptide deposition. Nat. Genet. 17, 263–264 (1997).

  40. 40.

    Irizarry, M. C. et al. Apolipoprotein E affects the amount, form, and anatomical distribution of amyloid beta-peptide deposition in homozygous APP(V717F) transgenic mice. Acta Neuropathol. 100, 451–458 (2000).

  41. 41.

    Lee, L., Kosuri, P. & Arancio, O. Picomolar amyloid-beta peptides enhance spontaneous astrocyte calcium transients. J. Alzheimers Dis. 38, 49–62 (2014).

  42. 42.

    Lim, D. et al. Amyloid beta deregulates astroglial mGluR5-mediated calcium signaling via calcineurin and Nf-kB. Glia 61, 1134–1145 (2013).

  43. 43.

    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).

  44. 44.

    Spires-Jones, T. L., Attems, J. & Thal, D. R. Interactions of pathological proteins in neurodegenerative diseases. Acta Neuropathol. 134, 187–205 (2017).

  45. 45.

    Serrano-Pozo, A. et al. Reactive glia not only associates with plaques but also parallels tangles in Alzheimer’s disease. Am. J. Pathol. 179, 1373–1384 (2011).

  46. 46.

    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).

  47. 47.

    Hampton, D. W. et al. Cell-mediated neuroprotection in a mouse model of human tauopathy. J. Neurosci. 30, 9973–9983 (2010).

  48. 48.

    Bemiller, S. M. et al. TREM2 deficiency exacerbates tau pathology through dysregulated kinase signaling in a mouse model of tauopathy. Mol. Neurodegener. 12, 74 (2017).

  49. 49.

    Jiang, T. et al. TREM2 modifies microglial phenotype and provides neuroprotection in P301S tau transgenic mice. Neuropharmacology 105, 196–206 (2016).

  50. 50.

    Shi, Y. et al. ApoE4 markedly exacerbates tau-mediated neurodegeneration in a mouse model of tauopathy. Nature 549, 523–527 (2017).

  51. 51.

    Asai, H. et al. Depletion of microglia and inhibition of exosome synthesis halt tau propagation. Nat. Neurosci. 18, 1584–1593 (2015).

  52. 52.

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

  53. 53.

    Nash, K. R. et al. Fractalkine overexpression suppresses tau pathology in a mouse model of tauopathy. Neurobiol. Aging 34, 1540–1548 (2013).

  54. 54.

    Grabert, K. et al. Microglial brain region-dependent diversity and selective regional sensitivities to aging. Nat. Neurosci. 19, 504–516 (2016).

  55. 55.

    Clarke, L. E. et al. Normal aging induces A1-like astrocyte reactivity. Proc. Natl Acad. Sci. 115, E1896–E1905 (2018).

  56. 56.

    Tzioras, M. et al. Assessing amyloid-β, tau, and glial features in Lothian Birth Cohort 1936 participants post-mortem. Matters (Zur). https://doi.org/10.19185/matters.201708000003 (2017).

  57. 57.

    Kang, S. S. et al. Microglial translational profiling reveals a convergent APOE pathway from aging, amyloid, and tau. J. Exp. Med. 215, 2235–2245 (2018).

  58. 58.

    Gomez-Isla, T. et al. Profound loss of layer II entorhinal cortex neurons occurs in very mild Alzheimer’s disease. J. Neurosci. 16, 4491–4500 (1996).

  59. 59.

    Mathys, H. et al. Temporal tracking of microglia activation in neurodegeneration at single-cell resolution. Cell Rep. 21, 366–380 (2017).

  60. 60.

    Park, J. et al. A 3D human triculture system modeling neurodegeneration and neuroinflammation in Alzheimer’s disease. Nat. Neurosci. 21, 941–951 (2018).

  61. 61.

    Henstridge, C. M. & Spires-Jones, T. L. Modeling Alzheimer’s disease brains in vitro. Nat. Neurosci. 21, 899–900 (2018).

  62. 62.

    Simard, A. R., Soulet, D., Gowing, G., Julien, J. P. & Rivest, S. Bone marrow-derived microglia play a critical role in restricting senile plaque formation in Alzheimer’s disease. Neuron 49, 489–502 (2006).

  63. 63.

    Stalder, A. K. et al. Invasion of hematopoietic cells into the brain of amyloid precursor protein transgenic mice. J. Neurosci. 25, 11125–11132 (2005).

  64. 64.

    Zuroff, L., Daley, D., Black, K. L. & Koronyo-Hamaoui, M. Clearance of cerebral Aβ in Alzheimer’s disease: reassessing the role of microglia and monocytes. Cell. Mol. Life Sci. 74, 2167–2201 (2017).

  65. 65.

    Buttini, M. et al. Cellular source of apolipoprotein E4 determines neuronal susceptibility to excitotoxic injury in transgenic mice. Am. J. Pathol. 177, 563–569 (2010).

  66. 66.

    Liddelow, S. A. et al. Neurotoxic reactive astrocytes are induced by activated microglia. Nature 541, 481–487 (2017).

  67. 67.

    Chakrabarty, P. et al. IL-10 alters immunoproteostasis in APP mice, increasing plaque burden and worsening cognitive behavior. Neuron 85, 519–533 (2015).

  68. 68.

    Guillot-Sestier, M. V. et al. Il10 deficiency rebalances innate immunity to mitigate Alzheimer-like pathology. Neuron 85, 534–548 (2015).

  69. 69.

    Lian, H. et al. Astrocyte-microglia cross talk through complement activation modulates amyloid pathology in mouse models of Alzheimer’s disease. J. Neurosci. 36, 577–589 (2016).

  70. 70.

    Sekar, S. et al. Alzheimer’s disease is associated with altered expression of genes involved in immune response and mitochondrial processes in astrocytes. Neurobiol. Aging 36, 583–591 (2015).

  71. 71.

    Mosher, K. I. & Wyss-Coray, T. Microglial dysfunction in brain aging and Alzheimer’s disease. Biochem. Pharmacol. 88, 594–604 (2014).

  72. 72.

    Liao, Y. F., Wang, B. J., Cheng, H. T., Kuo, L. H. & Wolfe, M. S. Tumor necrosis factor-alpha, interleukin-1beta, and interferon-gamma stimulate gamma-secretase-mediated cleavage of amyloid precursor protein through a JNK-dependent MAPK pathway. J. Biol. Chem. 279, 49523–49532 (2004).

  73. 73.

    Diniz, L. P. et al. Astrocyte transforming growth factor beta 1 protects synapses against Aβ oligomers in Alzheimer’s disease model. J. Neurosci. 37, 6797–6809 (2017).

  74. 74.

    White, J. A., Manelli, A. M., Holmberg, K. H., Van Eldik, L. J. & Ladu, M. J. Differential effects of oligomeric and fibrillar amyloid-beta 1–42 on astrocyte-mediated inflammation. Neurobiol. Dis. 18, 459–465 (2005).

  75. 75.

    Rodriguez, G. A., Tai, L. M. & LaDu, M. J. & Rebeck, G. W. Human APOE4 increases microglia reactivity at Aβ plaques in a mouse model of Aβ deposition. J. Neuroinflammation 11, 111 (2014).

  76. 76.

    He, P. et al. Deletion of tumor necrosis factor death receptor inhibits amyloid beta generation and prevents learning and memory deficits in Alzheimer’s mice. J. Cell Biol. 178, 829–841 (2007).

  77. 77.

    Wilkaniec, A., Gassowska-Dobrowolska, M., Strawski, M., Adamczyk, A. & Czapski, G. A. Inhibition of cyclin-dependent kinase 5 affects early neuroinflammatory signalling in murine model of amyloid beta toxicity. J. Neuroinflammation 15, 1 (2018).

  78. 78.

    Patel, N. S. et al. Inflammatory cytokine levels correlate with amyloid load in transgenic mouse models of Alzheimer’s disease. J. Neuroinflammation 2, 9 (2005).

  79. 79.

    Wood, L. B. et al. Identification of neurotoxic cytokines by profiling Alzheimer’s disease tissues and neuron culture viability screening. Sci. Rep. 5, 16622 (2015).

  80. 80.

    Robinson, S. R., Dobson, C. & Lyons, J. Challenges and directions for the pathogen hypothesis of Alzheimer’s disease. Neurobiol. Aging 25, 629–637 (2004).

  81. 81.

    Itzhaki, R. F. et al. Herpes simplex virus type 1 in brain and risk of Alzheimer’s disease. Lancet 349, 241–244 (1997).

  82. 82.

    Readhead, B. et al. Multiscale analysis of independent Alzheimer’s cohorts finds disruption of molecular, genetic, and clinical networks by human herpesvirus. Neuron 99, 64–82 (2018).

  83. 83.

    Eimer, W. A. et al. Alzheimer’s disease-associated beta-amyloid is rapidly seeded by herpesviridae to protect against brain infection. Neuron 99, 56–63 (2018).

  84. 84.

    Kumar, D. K. et al. Amyloid-beta peptide protects against microbial infection in mouse and worm models of Alzheimer’s disease. Sci. Transl Med. 8, 340ra372 (2016).

  85. 85.

    Dean, D. C. 3rd et al. Association of amyloid pathology with myelin alteration in preclinical Alzheimer disease. JAMA Neurol. 74, 41–49 (2017).

  86. 86.

    McAleese, K. E. et al. Cortical tau load is associated with white matter hyperintensities. Acta Neuropathol. Commun. 3, 60 (2015).

  87. 87.

    Braak, H. & Braak, E. Development of Alzheimer-related neurofibrillary changes in the neocortex inversely recapitulates cortical myelogenesis. Acta Neuropathol. 92, 197–201 (1996).

  88. 88.

    de Faria, O. et al. Neuroglial interactions underpinning myelin plasticity. Dev. Neurobiol. 78, 93–107 (2018).

  89. 89.

    Xu, J. et al. Amyloid-beta peptides are cytotoxic to oligodendrocytes. J. Neurosci. 21, RC118 (2001).

  90. 90.

    Jantaratnotai, N., Ryu, J. K., Kim, S. U. & McLarnon, J. G. Amyloid beta peptide-induced corpus callosum damage and glial activation in vivo. Neuroreport 14, 1429–1433 (2003).

  91. 91.

    Miron, V. E. et al. M2 microglia and macrophages drive oligodendrocyte differentiation during CNS remyelination. Nat. Neurosci. 16, 1211–1218 (2013).

  92. 92.

    Terry, R. D. et al. Physical basis of cognitive alterations in Alzheimer’s disease: synapse loss is the major correlate of cognitive impairment. Ann. Neurol. 30, 572–580 (1991).

  93. 93.

    Akram, A. et al. Stereologic estimates of total spinophilin-immunoreactive spine number in area 9 and the CA1 field: relationship with the progression of Alzheimer’s disease. Neurobiol. Aging 29, 1296–1307 (2008).

  94. 94.

    Mufson, E. J. et al. Mild cognitive impairment: pathology and mechanisms. Acta Neuropathol. 123, 13–30 (2012).

  95. 95.

    Scheff, S. W., DeKosky, S. T. & Price, D. A. Quantitative assessment of cortical synaptic density in Alzheimer’s disease. Neurobiol. Aging 11, 29–37 (1990).

  96. 96.

    DeKosky, S. T. & Scheff, S. W. Synapse loss in frontal cortex biopsies in Alzheimer’s disease: correlation with cognitive severity. Ann. Neurol. 27, 457–464 (1990). This paper presents the first study to demonstrate that loss of synapses correlates with cognitive decline in AD using elegant electron microscopy imaging of frontal cortex biopsy sample tissue.

  97. 97.

    Spires-Jones, T. L. & Hyman, B. T. The intersection of amyloid beta and tau at synapses in Alzheimer’s disease. Neuron 82, 756–771 (2014).

  98. 98.

    Henstridge, C. M., Pickett, E. & Spires-Jones, T. L. Synaptic pathology: A shared mechanism in neurological disease. Ageing Res. Rev. 28, 72–84 (2016).

  99. 99.

    Chung, W. S. et al. Astrocytes mediate synapse elimination through MEGF10 and MERTK pathways. Nature 504, 394–400 (2013).

  100. 100.

    Salter, M. W. & Stevens, B. Microglia emerge as central players in brain disease. Nat. Med. 23, 1018–1027 (2017).

  101. 101.

    Schafer, D. P., Lehrman, E. K. & Stevens, B. The “quad-partite” synapse: microglia-synapse interactions in the developing and mature CNS. Glia 61, 24–36 (2013).

  102. 102.

    Tremblay, M. E., Lowery, R. L. & Majewska, A. K. Microglial interactions with synapses are modulated by visual experience. PLOS Biol. 8, e1000527 (2010).

  103. 103.

    Paolicelli, R. C. et al. Synaptic pruning by microglia is necessary for normal brain development. Science 333, 1456–1458 (2011).

  104. 104.

    Schafer, D. P. et al. Microglia sculpt postnatal neural circuits in an activity and complement-dependent manner. Neuron 74, 691–705 (2012).

  105. 105.

    Stevens, B. et al. The classical complement cascade mediates CNS synapse elimination. Cell 131, 1164–1178 (2007).

  106. 106.

    Stephan, A. H., Barres, B. A. & Stevens, B. The complement system: an unexpected role in synaptic pruning during development and disease. Annu. Rev. Neurosci. 35, 369–389 (2012).

  107. 107.

    Bialas, A. R. & Stevens, B. TGF-β signaling regulates neuronal C1q expression and developmental synaptic refinement. Nat. Neurosci. 16, 1773–1782 (2013).

  108. 108.

    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).

  109. 109.

    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).

  110. 110.

    Yasojima, K., Schwab, C., McGeer, E. G. & McGeer, P. L. Up-regulated production and activation of the complement system in Alzheimer’s disease brain. Am. J. Pathol. 154, 927–936 (1999).

  111. 111.

    Hong, S. et al. Complement and microglia mediate early synapse loss in Alzheimer mouse models. Science 352, 712–716 (2016). This study is the first demonstration of complement-mediated microglial engulfment of synapses in AD mouse models.

  112. 112.

    Shi, Q. et al. Complement C3 deficiency protects against neurodegeneration in aged plaque-rich APP/PS1 mice. Sci. Transl Med. 9, eaaf6295 (2017). This paper establishes the first link between APOE and tau-induced neurodegeneration in an FTD model. APOE knockout was protective whereas APOE2<APOE3<APOE4 expression was associated with reduced homeostatic and increased pro-inflammatory gene expression in both microglia and astrocytes.

  113. 113.

    Weinhard, L. et al. Microglia remodel synapses by presynaptic trogocytosis and spine head filopodia induction. Nat. Commun. 9, 1228 (2018).

  114. 114.

    Boulanger, L. M. Immune proteins in brain development and synaptic plasticity. Neuron 64, 93–109 (2009).

  115. 115.

    Syken, J., Grandpre, T., Kanold, P. O. & Shatz, C. J. PirB restricts ocular-dominance plasticity in visual cortex. Science 313, 1795–1800 (2006).

  116. 116.

    William, C. M. et al. Synaptic plasticity defect following visual deprivation in Alzheimer’s disease model transgenic mice. J. Neurosci. 32, 8004–8011 (2012).

  117. 117.

    Kim, T. et al. Human LilrB2 is a beta-amyloid receptor and its murine homolog PirB regulates synaptic plasticity in an Alzheimer’s model. Science 341, 1399–1404 (2013).

  118. 118.

    Paolicelli, R. C. et al. TDP-43 depletion in microglia promotes amyloid clearance but also induces synapse loss. Neuron 95, 297–308 (2017).

  119. 119.

    Henstridge, C. M. et al. Synapse loss in the prefrontal cortex is associated with cognitive decline in amyotrophic lateral sclerosis. Acta Neuropathol. 135, 213–226 (2018).

  120. 120.

    Matos, M., Augusto, E., Agostinho, P., Cunha, R. A. & Chen, J. F. Antagonistic interaction between adenosine A2A receptors and Na+/K+-ATPase-α2 controlling glutamate uptake in astrocytes. J. Neurosci. 33, 18492–18502 (2013).

  121. 121.

    Orr, A. G. et al. Astrocytic adenosine receptor A2A and Gs-coupled signaling regulate memory. Nat. Neurosci. 18, 423–434 (2015).

  122. 122.

    Mookherjee, P. et al. GLT-1 loss accelerates cognitive deficit onset in an Alzheimer’s disease animal model. J. Alzheimers Dis. 26, 447–455 (2011).

  123. 123.

    Scimemi, A. et al. Amyloid-β1-42 slows clearance of synaptically released glutamate by mislocalizing astrocytic GLT-1. J. Neurosci. 33, 5312–5318 (2013).

  124. 124.

    Zumkehr, J. et al. Ceftriaxone ameliorates tau pathology and cognitive decline via restoration of glial glutamate transporter in a mouse model of Alzheimer’s disease. Neurobiol. Aging 36, 2260–2271 (2015).

  125. 125.

    Reisberg, B. et al. Memantine in moderate-to-severe Alzheimer’s disease. N. Engl. J. Med. 348, 1333–1341 (2003).

  126. 126.

    Pitas, R. E., Boyles, J. K., Lee, S. H., Foss, D. & Mahley, R. W. Astrocytes synthesize apolipoprotein E and metabolize apolipoprotein E-containing lipoproteins. Biochim. Biophys. Acta 917, 148–161 (1987).

  127. 127.

    Koffie, R. M. et al. Apolipoprotein E4 effects in Alzheimer’s disease are mediated by synaptotoxic oligomeric amyloid-beta. Brain: J. Neurol. 135, 2155–2168 (2012). This study applies, for the first time, the high-resolution imaging technique of array tomography to human brain tissue. APOE4 was observed to increase the presence of oligomeric Aβ at synapses in the AD brain.

  128. 128.

    Rebeck, G. W., Reiter, J. S., Strickland, D. K. & Hyman, B. T. Apolipoprotein E in sporadic Alzheimer’s disease: allelic variation and receptor interactions. Neuron 11, 575–580 (1993).

  129. 129.

    Castellano, J. M. et al. Human apoE isoforms differentially regulate brain amyloid-β peptide clearance. Sci. Transl Med. 3, 89ra57 (2011).

  130. 130.

    Hashimoto, T. et al. Apolipoprotein E, especially apolipoprotein E4, increases the oligomerization of amyloid β peptide. J. Neurosci. 32, 15181–15192 (2012).

  131. 131.

    Klein, W. Synaptotoxic amyloid-β oligomers: a molecular basis for the cause, diagnosis, and treatment of Alzheimer’s disease? J. Alzheimers Dis. 33 (Suppl. 1), 49–65 (2013).

  132. 132.

    Perez-Nievas, B. G. et al. Dissecting phenotypic traits linked to human resilience to Alzheimer’s pathology. Brain 136, 2510–2526 (2013).

  133. 133.

    Dumanis, S. B. et al. ApoE4 decreases spine density and dendritic complexity in cortical neurons in vivo. J. Neurosci. 29, 15317–15322 (2009).

  134. 134.

    Dumanis, S. B., DiBattista, A. M., Miessau, M., Moussa, C. E. & Rebeck, G. W. APOE genotype affects the pre-synaptic compartment of glutamatergic nerve terminals. J. Neurochem. 124, 4–14 (2013).

  135. 135.

    Korwek, K. M., Trotter, J. H., Ladu, M. J., Sullivan, P. M. & Weeber, E. J. ApoE isoform-dependent changes in hippocampal synaptic function. Mol. Neurodegener. 4, 21 (2009).

  136. 136.

    Schiepers, O. J. et al. APOE E4 status predicts age-related cognitive decline in the ninth decade: longitudinal follow-up of the Lothian Birth Cohort 1921. Mol. Psychiatry 17, 315–324 (2012).

  137. 137.

    Henstridge, C. M. et al. Post-mortem brain analyses of the Lothian Birth Cohort 1936: extending lifetime cognitive and brain phenotyping to the level of the synapse. Acta Neuropathol. Commun. 3, 53 (2015).

  138. 138.

    Kay, K. R. et al. Studying synapses in human brain with array tomography and electron microscopy. Nat. Protoc. 8, 1366–1380 (2013).

  139. 139.

    Yoshiyama, Y. et al. Synapse loss and microglial activation precede tangles in a P301S tauopathy mouse model. Neuron 53, 337–351 (2007).

  140. 140.

    Sidoryk-Wegrzynowicz, M. et al. Astrocytes in mouse models of tauopathies acquire early deficits and lose neurosupportive functions. Acta Neuropathol. Commun. 5, 89 (2017).

  141. 141.

    Hunsberger, H. C., Rudy, C. C., Batten, S. R., Gerhardt, G. A. & Reed, M. N. P301L tau expression affects glutamate release and clearance in the hippocampal trisynaptic pathway. J. Neurochem. 132, 169–182 (2015).

  142. 142.

    Piacentini, R. et al. Reduced gliotransmitter release from astrocytes mediates tau-induced synaptic dysfunction in cultured hippocampal neurons. Glia 65, 1302–1316 (2017).

  143. 143.

    Dudvarski Stankovic, N., Teodorczyk, M., Ploen, R., Zipp, F. & Schmidt, M. H. H. Microglia-blood vessel interactions: a double-edged sword in brain pathologies. Acta Neuropathol. 131, 347–363 (2016).

  144. 144.

    Shen, Q., Goderie, S. K., Jin, L., Karanth, N. & Sun, Y. Endothelial cells stimulate self-renewal and expand neurogenesis of neural stem cells. Science 304, 1338–1340 (2004).

  145. 145.

    Arai, K. & Lo, E. H. An oligovascular niche: cerebral endothelial cells promote the survival and proliferation of oligodendrocyte precursor cells. J. Neurosci. 29, 4351–4355 (2009).

  146. 146.

    Guo, S., Kim, W. J., Lok, J. & Lee, S. R. Neuroprotection via matrix-trophic coupling between cerebral endothelial cells and neurons. Proc. Natl Acad. Sci. USA 105, 7582–7587 (2008).

  147. 147.

    Santos, C. Y. et al. Pathophysiologic relationship between Alzheimer’s disease, cerebrovascular disease, and cardiovascular risk: a review and synthesis. Alzheimers Dement. (Amst.) 7, 69–87 (2017).

  148. 148.

    Matthews, F. E. et al. A two decade dementia incidence comparison from the cognitive function and ageing studies I and II. Nat. Commun. 7, 11398 (2016).

  149. 149.

    Iadecola, C. et al. SOD1 rescues cerebral endothelial dysfunction in mice overexpressing amyloid precursor protein. Nat. Neurosci. 2, 157–161 (1999).

  150. 150.

    Iadecola, C. Neurovascular regulation in the normal brain and in Alzheimer’s disease. Nat. Rev. Neurosci. 5, 347–360 (2004).

  151. 151.

    Kelly, P. et al. Microvascular ultrastructural changes precede cognitive impairment in the murine APPswe/PS1dE9 model of Alzheimer’s disease. Angiogenesis 20, 567–580 (2017).

  152. 152.

    Wang, H., Golob, E. J. & Su, M.-Y. Y. Vascular volume and blood-brain barrier permeability measured by dynamic contrast enhanced MRI in hippocampus and cerebellum of patients with MCI and normal controls. J. Magn. Reson. Imaging 24, 695–700 (2006).

  153. 153.

    Starr, J. M., Farrall, A. J., Armitage, P. & McGurn, B. Blood–brain barrier permeability in Alzheimer’s disease: a case–control MRI study. Psychiatry Res. 171, 232–241 (2009).

  154. 154.

    Jagust, W. J. et al. Diminished glucose transport in Alzheimer’s disease: dynamic PET studies. J. Cereb. Blood Flow Metab. 11, 323–330 (1991).

  155. 155.

    Iturria-Medina, Y. et al. Early role of vascular dysregulation on late-onset Alzheimer’s disease based on multifactorial data-driven analysis. Nat. Commun. 7, 11934 (2016).

  156. 156.

    Wardlaw, J. M. & Hernández, M. C. V. What are white matter hyperintensities made of? Relevance to vascular cognitive impairment. J. Am. Heart Assoc. 4, e001140 (2015).

  157. 157.

    McAleese, K. E. et al. Parietal white matter lesions in Alzheimer’s disease are associated with cortical neurodegenerative pathology, but not with small vessel disease. Acta Neuropathol. 134, 459–473 (2017).

  158. 158.

    Lee, S. et al. White matter hyperintensities are a core feature of Alzheimer’s disease: evidence from the dominantly inherited Alzheimer network. Ann. Neurol. 79, 929–939 (2016).

  159. 159.

    Bakker, E. N. et al. Lymphatic clearance of the brain: perivascular, paravascular and significance for neurodegenerative diseases. Cell. Mol. Neurobiol. 36, 181–194 (2016).

  160. 160.

    Tarasoff-Conway, J. M. et al. Clearance systems in the brain-implications for Alzheimer disease. Nat. Rev. Neurol. 11, 457–470 (2015).

  161. 161.

    Iadecola, C. The neurovascular unit coming of age: a journey through neurovascular coupling in health and disease. Neuron 96, 17–42 (2017).

  162. 162.

    Iliff, J. J. et al. A paravascular pathway facilitates CSF flow through the brain parenchyma and the clearance of interstitial solutes, including amyloid beta. Sci. Transl Med. 4, 147ra111 (2012).

  163. 163.

    Plog, B. A. & Nedergaard, M. The glymphatic system in central nervous system health and disease: past, present, and future. Annu. Rev. Pathol. 13, 379–394 (2018).

  164. 164.

    Da Mesquita, S. et al. Functional aspects of meningeal lymphatics in ageing and Alzheimer’s disease. Nature 560, 185–191 (2018).

  165. 165.

    Lucey, B. P. et al. Associations between beta-amyloid kinetics and the beta-amyloid diurnal pattern in the central nervous system. JAMA Neurol. 74, 207–215 (2017).

  166. 166.

    Kang, J. E. et al. Amyloid-beta dynamics are regulated by orexin and the sleep-wake cycle. Science 326, 1005–1007 (2009).

  167. 167.

    Bero, A. W. et al. Neuronal activity regulates the regional vulnerability to amyloid-beta deposition. Nat. Neurosci. 14, 750–756 (2011).

  168. 168.

    Xie, L. et al. Sleep drives metabolite clearance from the adult brain. Science 342, 373–377 (2013).

  169. 169.

    Zhao, Z. et al. Central role for PICALM in amyloid-beta blood-brain barrier transcytosis and clearance. Nat. Neurosci. 18, 978–987 (2015).

  170. 170.

    Nelson, A. R., Sagare, A. P. & Zlokovic, B. V. Role of clusterin in the brain vascular clearance of amyloid-beta. Proc. Natl Acad. Sci. USA 114, 8681–8682 (2017).

  171. 171.

    Robert, J. et al. Clearance of beta-amyloid is facilitated by apolipoprotein E and circulating high-density lipoproteins in bioengineered human vessels. eLife 6, e29595 (2017).

  172. 172.

    Burfeind, K. G. et al. The effects of noncoding aquaporin-4 single-nucleotide polymorphisms on cognition and functional progression of Alzheimer’s disease. Alzheimers Dement. (NY) 3, 348–359 (2017).

  173. 173.

    Sagare, A. P. et al. Pericyte loss influences Alzheimer-like neurodegeneration in mice. Nat. Commun. 4, 2932 (2013).

  174. 174.

    Hill, R. A. et al. Regional blood flow in the normal and ischemic brain is controlled by arteriolar smooth muscle cell contractility and not by capillary pericytes. Neuron 87, 95–110 (2015).

  175. 175.

    Faraco, G. et al. Hypertension enhances Aβ-induced neurovascular dysfunction, promotes β-secretase activity, and leads to amyloidogenic processing of APP. J. Cereb. Blood Flow Metab. 36, 241–252 (2016).

  176. 176.

    El Khoury, J. et al. Ccr2 deficiency impairs microglial accumulation and accelerates progression of Alzheimer-like disease. Nat. Med. 13, 432–438 (2007).

  177. 177.

    Jiang, T., Sun, Q. & Chen, S. Oxidative stress: a major pathogenesis and potential therapeutic target of antioxidative agents in Parkinson’s disease and Alzheimer’s disease. Prog. Neurobiol. 147, 1–19 (2016).

  178. 178.

    Pratico, D. Oxidative stress hypothesis in Alzheimer’s disease: a reappraisal. Trends Pharmacol. Sci. 29, 609–615 (2008).

  179. 179.

    Pratico, D., Uryu, K., Leight, S., Trojanoswki, J. Q. & Lee, V. M. Increased lipid peroxidation precedes amyloid plaque formation in an animal model of Alzheimer amyloidosis. J. Neurosci. 21, 4183–4187 (2001).

  180. 180.

    Matsuoka, Y., Picciano, M., La Francois, J. & Duff, K. Fibrillar beta-amyloid evokes oxidative damage in a transgenic mouse model of Alzheimer’s disease. Neuroscience 104, 609–613 (2001).

  181. 181.

    Nunomura, A. et al. Oxidative damage is the earliest event in Alzheimer disease. J. Neuropathol. Exp. Neurol. 60, 759–767 (2001).

  182. 182.

    Park, L. et al. Nox2-derived radicals contribute to neurovascular and behavioral dysfunction in mice overexpressing the amyloid precursor protein. Proc. Natl Acad. Sci. USA 105, 1347–1352 (2008).

  183. 183.

    Park, L. et al. Innate immunity receptor CD36 promotes cerebral amyloid angiopathy. Proc. Natl Acad. Sci. USA 110, 3089–3094 (2013).

  184. 184.

    Park, L. et al. Brain perivascular macrophages initiate the neurovascular dysfunction of Alzheimer Aβ peptides. Circ. Res. 121, 258–269 (2017).

  185. 185.

    Lane-Donovan, C. & Herz, J. ApoE, ApoE receptors, and the synapse in Alzheimer’s disease. Trends Endocrinol. Metab. 28, 273–284 (2017).

  186. 186.

    Cramer, P. E. et al. ApoE-directed therapeutics rapidly clear beta-amyloid and reverse deficits in AD mouse models. Science 335, 1503–1506 (2012).

  187. 187.

    Tesseur, I. et al. Comment on “ApoE-directed therapeutics rapidly clear beta-amyloid and reverse deficits in AD mouse models”. Science 340, 924 (2013).

  188. 188.

    LaClair, K. D. et al. Treatment with bexarotene, a compound that increases apolipoprotein-E, provides no cognitive benefit in mutant APP/PS1 mice. Mol. Neurodegener. 8, 18 (2013).

  189. 189.

    O’Hare, E. et al. Lack of support for bexarotene as a treatment for Alzheimer’s disease. Neuropharmacology 100, 124–130 (2016).

  190. 190.

    Cummings, J. L. et al. Double-blind, placebo-controlled, proof-of-concept trial of bexarotene Xin moderate Alzheimer’s disease. Alzheimers Res. Ther. 8, 4 (2016).

  191. 191.

    Huynh, T. V. et al. Age-dependent effects of apoE reduction using antisense oligonucleotides in a model of beta-amyloidosis. Neuron 96, 1013–1023 (2017).

  192. 192.

    in t’ Veld, B. A. et al. Nonsteroidal antiinflammatory drugs and the risk of Alzheimer’s disease. N. Engl. J. Med. 345, 1515–1521 (2001).

  193. 193.

    Masgrau, R., Guaza, C., Ransohoff, R. M. & Galea, E. Should we stop saying ‘glia’ and ‘neuroinflammation’? Trends Mol. Med. 23, 486–500 (2017).

  194. 194.

    Breitner, J. C. et al. Extended results of the Alzheimer’s disease anti-inflammatory prevention trial. Alzheimers Dement. 7, 402–411 (2011).

  195. 195.

    Lansita, J. A. et al. Nonclinical development of ANX005: a humanized anti-C1q antibody for treatment of autoimmune and neurodegenerative diseases. Int. J. Toxicol. 36, 449–462 (2017).

  196. 196.

    Femminella, G. D. et al. Antidiabetic drugs in Alzheimer’s disease: mechanisms of action and future perspectives. J. Diabetes Res. 2017, 7420796 (2017).

  197. 197.

    Infante-Garcia, C. et al. Antidiabetic polypill improves central pathology and cognitive impairment in a mixed model of Alzheimer’s disease and type 2 diabetes. Mol. Neurobiol. 55, 6130–6144 (2017).

  198. 198.

    Ramos-Rodriguez, J. J. et al. Progressive neuronal pathology and synaptic loss induced by prediabetes and type 2 diabetes in a mouse model of Alzheimer’s disease. Mol. Neurobiol. 54, 3428–3438 (2017).

  199. 199.

    Harrington, C. et al. Rosiglitazone does not improve cognition or global function when used as adjunctive therapy to AChE inhibitors in mild-to-moderate Alzheimer’s disease: two phase 3 studies. Curr. Alzheimer Res. 8, 592–606 (2011).

  200. 200.

    Takeda Pharmaceutical Company. Takeda and Zinfandel pharmaceuticals discontinue TOMMORROW trial following planned futility analysis. Takeda https://www.takeda.com/newsroom/newsreleases/2018/takeda-tommorrow-trial/ (2018).

  201. 201.

    Wu, Y. T. et al. The changing prevalence and incidence of dementia over time - current evidence. Nat. Rev. Neurol. 13, 327–339 (2017).

  202. 202.

    Hamer, M., Muniz Terrera, G. & Demakakos, P. Physical activity and trajectories in cognitive function: English longitudinal study of ageing. J. Epidemiol. Community Health 72, 477–483 (2018).

  203. 203.

    Forbes, D., Forbes, S. C., Blake, C. M., Thiessen, E. J. & Forbes, S. Exercise programs for people with dementia. Cochrane Database Syst. Rev. 4, CD006489 (2015).

  204. 204.

    Young, J., Angevaren, M., Rusted, J. & Tabet, N. Aerobic exercise to improve cognitive function in older people without known cognitive impairment. Cochrane Database Syst. Rev. 4, CD005381 (2015).

  205. 205.

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

  206. 206.

    Alzheimer, A. Ubereine eigenartige Erkrankung der Hirnrinde [German]. Allgemeine Zeitschrift Psychiatrie Psychisch-Gerichtliche Medizin 64, 146–148 (1907).

  207. 207.

    Hyman, B. T. et al. National Institute on Aging-Alzheimer’s Association guidelines for the neuropathologic assessment of Alzheimer’s disease. Alzheimers Dement. 8, 1–13 (2012).

  208. 208.

    De Strooper, B. et al. Deficiency of presenilin-1 inhibits the normal cleavage of amyloid precursor protein. Nature 391, 387–390 (1998).

  209. 209.

    Vassar, R. et al. Beta-secretase cleavage of Alzheimer’s amyloid precursor protein by the transmembrane aspartic protease BACE. Science 286, 735–741 (1999).

  210. 210.

    Thal, D. R., Rüb, U., Orantes, M. & Braak, H. Phases of Aβ-deposition in the human brain and its relevance for the development of AD. Neurology 58, 1791–1800 (2002).

  211. 211.

    Jarosz-Griffiths, H. H., Noble, E., Rushworth, J. V. & Hooper, N. M. Amyloid-β receptors: the good, the bad, and the prion protein. J. Biol. Chem. 291, 3174–3183 (2016).

  212. 212.

    Goedert, M., Spillantini, M. G., Cairns, N. J. & Crowther, R. A. Tau proteins of Alzheimer paired helical filaments: abnormal phosphorylation of all six brain isoforms. Neuron 8, 159–168 (1992).

  213. 213.

    Goedert, M. & Spillantini, M. G. A century of Alzheimer’s disease. Science 314, 777–781 (2006).

  214. 214.

    Hyman, B. T., Van Hoesen, G. W., Damasio, A. R. & Barnes, C. L. Alzheimer’s disease: cell-specific pathology isolates the hippocampal formation. Science 225, 1168–1170 (1984).

  215. 215.

    Braak, H. & Braak, E. Neuropathological stageing of Alzheimer-related changes. Acta Neuropathol. 82, 239–259 (1991).

  216. 216.

    Ingelsson, M. et al. Early Aβ accumulation and progressive synaptic loss, gliosis, and tangle formation in AD brain. Neurology 62, 925–931 (2004).

  217. 217.

    Nelson, P. T. et al. Correlation of Alzheimer disease neuropathologic changes with cognitive status: a review of the literature. J. Neuropathol. Exp. Neurol. 71, 362–381 (2012).

  218. 218.

    Gomez-Isla, T. et al. Neuronal loss correlates with but exceeds neurofibrillary tangles in Alzheimer’s disease. Ann. Neurol. 41, 17–24 (1997).

  219. 219.

    Dickerson, B. C., Stoub, T. R., Shah, R. C. & Sperling, R. A. Alzheimer-signature MRI biomarker predicts AD dementia in cognitively normal adults. Neurology 76, 1395–1402 (2011).

  220. 220.

    Hickman, S., Izzy, S., Sen, P., Morsett, L. & El Khoury, J. Microglia in neurodegeneration. Nat. Neurosci. 21, 1359–1369 (2018).

  221. 221.

    Heppner, F. L., Ransohoff, R. M. & Becher, B. Immune attack: the role of inflammation in Alzheimer disease. Nat. Rev. Neurosci. 16, 358–372 (2015).

  222. 222.

    Pekny, M. et al. Astrocytes: a central element in neurological diseases. Acta Neuropathol. 131, 323–345 (2016).

  223. 223.

    Rodriguez-Arellano, J. J., Parpura, V., Zorec, R. & Verkhratsky, A. Astrocytes in physiological aging and Alzheimer’s disease. Neuroscience 323, 170–182 (2016).

  224. 224.

    Cai, Z. & Xiao, M. Oligodendrocytes and Alzheimer’s disease. Int. J. Neurosci. 126, 97–104 (2016).

  225. 225.

    Nasrabady, S. E., Rizvi, B., Goldman, J. E. & Brickman, A. M. White matter changes in Alzheimer’s disease: a focus on myelin and oligodendrocytes. Acta Neuropathol. Commun. 6, 22 (2018).

  226. 226.

    Palop, J. J. & Mucke, L. Amyloid-beta-induced neuronal dysfunction in Alzheimer’s disease: from synapses toward neural networks. Nat. Neurosci. 13, 812–818 (2010).

  227. 227.

    Lambert, J. C. et al. Meta-analysis of 74,046 individuals identifies 11 new susceptibility loci for Alzheimer’s disease. Nat. Genet. 45, 1452–1458 (2013).

  228. 228.

    Hollingworth, P. et al. Common variants at ABCA7, MS4A6A/MS4A4E, EPHA1, CD33 and CD2AP are associated with Alzheimer’s disease. Nat. Genet. 43, 429–435 (2011).

  229. 229.

    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).

  230. 230.

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

  231. 231.

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

  232. 232.

    Sims, R. et al. Rare coding variants in PLCG2, ABI3, and TREM2 implicate microglial-mediated innate immunity in Alzheimer’s disease. Nat. Genet. 49, 1373–1384 (2017).

  233. 233.

    Robinson, M., Lee, B. Y. & Hane, F. T. Recent progress in Alzheimer’s disease research, part 2: genetics and epidemiology. J. Alzheimers Dis. 57, 317–330 (2017).

  234. 234.

    Efthymiou, A. G. & Goate, A. M. Late onset Alzheimer’s disease genetics implicates microglial pathways in disease risk. Mol. Neurodegener. 12, 43 (2017).

  235. 235.

    Zhang, Y. et al. An RNA-sequencing transcriptome and splicing database of glia, neurons, and vascular cells of the cerebral cortex. J. Neurosci. 34, 11929–11947 (2014).

Download references

Acknowledgements

T.L.S.-J. and C.M.H. gratefully acknowledge funding from the UK Dementia Research Institute, the European Research Council (ALZSYN), Alzheimer’s Research UK, the Alzheimer’s Society, MND Scotland and the Euan MacDonald Centre for Motorneurone Disease Research. T.L.S.-J. is a member of the FENS Kavli Network of Excellence. The authors thank M. Tzioras for excellent critical review of the manuscript.

Reviewer information

Nature Reviews Neuroscience thanks O. Arancio and the other anonymous reviewer(s) for their contribution to the peer review of this work.

Author information

Affiliations

  1. The University of Edinburgh Centre for Discovery Brain Sciences, UK Dementia Research Institute, Edinburgh, UK

    • Christopher M. Henstridge
    •  & Tara L. Spires-Jones
  2. MassGeneral Institute for Neurodegenerative Disease, Massachusetts General Hospital and Harvard Medical School, Charlestown, MA, USA

    • Bradley T. Hyman

Authors

  1. Search for Christopher M. Henstridge in:

  2. Search for Bradley T. Hyman in:

  3. Search for Tara L. Spires-Jones in:

Contributions

T.L.S.-J., B.T.H. and C.M.H. made substantial contributions to the discussion of content, writing, review and editing of the manuscript before submission.

Competing interests

The authors declare no competing interests.

Corresponding author

Correspondence to Tara L. Spires-Jones.

Glossary

Amyloid cascade hypothesis

Initially proposed in 1992, this hypothesis posits that the accumulation of amyloid-β (Aβ) is the initiating factor in Alzheimer disease pathogenesis, leading to the formation of amyloid plaques, neurofibrillary tangles, neuron loss and clinical dementia.

Innate immune system

Reactive response that utilizes chemical mediators to fight infection and clear foreign substances from the body by recruiting specialized immune cells. It can also activate a second wave of adaptive immune response by presenting antigens to adaptive immune cells.

Secretomes

The secretome includes all secretable factors released from a cell.

Oligomeric Aβ

Single molecules of Aβ are known as monomers. These monomers can aggregate to form oligomeric structures of two or more monomers, which can then accumulate into larger fibrillar forms of Aβ and deposit as the hallmark amyloid plaques.

Cytokine

Small releasable signalling proteins that often have immunomodulatory effects. These include chemokines, interleukins and interferons and they can be released by numerous immune cell types, endothelial cells and fibroblasts.

Homeostatic genes

Genes encoding a protein involved in a homeostatic mechanism within the cell.

Glymphatic system

Drainage pathway found in the vertebrate CNS that allows cerebrospinal fluid to enter the brain alongside penetrating arteries and facilitates the removal of interstitial fluid and waste products from the brain.

About this article

Publication history

Published

DOI

https://doi.org/10.1038/s41583-018-0113-1