Rapid appearance and local toxicity of amyloid-β plaques in a mouse model of Alzheimer’s disease

Abstract

Senile plaques accumulate over the course of decades in the brains of patients with Alzheimer’s disease. A fundamental tenet of the amyloid hypothesis of Alzheimer’s disease is that the deposition of amyloid-β precedes and induces the neuronal abnormalities that underlie dementia1. This idea has been challenged, however, by the suggestion that alterations in axonal trafficking and morphological abnormalities precede and lead to senile plaques2. The role of microglia in accelerating or retarding these processes has been uncertain. To investigate the temporal relation between plaque formation and the changes in local neuritic architecture, we used longitudinal in vivo multiphoton microscopy to sequentially image young APPswe/PS1d9xYFP (B6C3-YFP) transgenic mice3. Here we show that plaques form extraordinarily quickly, over 24 h. Within 1–2 days of a new plaque’s appearance, microglia are activated and recruited to the site. Progressive neuritic changes ensue, leading to increasingly dysmorphic neurites over the next days to weeks. These data establish plaques as a critical mediator of neuritic pathology.

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Figure 1: Appearance of a novel plaque is a rapid process.
Figure 2: Microglia recruitment follows plaque formation.
Figure 3: Plaque formation has no immediate effect on neuritic curvature.

References

  1. 1

    Hardy, J. & Selkoe, D. J. The amyloid hypothesis of Alzheimer’s disease: progress and problems on the road to therapeutics. Science 297, 353–356 (2002)

    CAS  Article  ADS  PubMed  Google Scholar 

  2. 2

    Stokin, G. B. et al. Axonopathy and transport deficits early in the pathogenesis of Alzheimer’s disease. Science 307, 1282–1288 (2005)

    CAS  Article  ADS  PubMed  Google Scholar 

  3. 3

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

    CAS  Article  PubMed  Google Scholar 

  4. 4

    Jankowsky, J. L. et al. Mutant presenilins specifically elevate the levels of the 42 residue beta-amyloid peptide in vivo: evidence for augmentation of a 42-specific gamma secretase. Hum. Mol. Genet. 13, 159–170 (2004)

    CAS  Article  PubMed  Google Scholar 

  5. 5

    Kawai, M., Kalaria, R. N., Harik, S. I. & Perry, G. The relationship of amyloid plaques to cerebral capillaries in Alzheimer’s disease. Am. J. Pathol. 137, 1435–1446 (1990)

    CAS  PubMed  PubMed Central  Google Scholar 

  6. 6

    Kumar-Singh, S. et al. Dense-core plaques in Tg2576 and PSAPP mouse models of Alzheimer’s disease are centered on vessel walls. Am. J. Pathol. 167, 527–543 (2005)

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  7. 7

    Hsiao, K. et al. Correlative memory deficits, Aβ elevation, and amyloid plaques in transgenic mice. Science 274, 99–102 (1996)

    CAS  Article  ADS  PubMed  Google Scholar 

  8. 8

    Hyman, B. T. et al. Quantitative analysis of senile plaques in Alzheimer disease: observation of log-normal size distribution and molecular epidemiology of differences associated with apolipoprotein E genotype and trisomy 21 (Down syndrome). Proc. Natl Acad. Sci. USA 92, 3586–3590 (1995)

    CAS  Article  ADS  PubMed  Google Scholar 

  9. 9

    Itagaki, S., McGeer, P. L., Akiyama, H., Zhu, S. & Selkoe, D. Relationship of microglia and astrocytes to amyloid deposits of Alzheimer disease. J. Neuroimmunol. 24, 173–182 (1989)

    CAS  Article  PubMed  Google Scholar 

  10. 10

    Frautschy, S. A. et al. Microglial response to amyloid plaques in APPsw transgenic mice. Am. J. Pathol. 152, 307–317 (1998)

    CAS  PubMed  PubMed Central  Google Scholar 

  11. 11

    Combs, C. K., Karlo, J. C., Kao, S. C. & Landreth, G. E. β-Amyloid stimulation of microglia and monocytes results in TNFα-dependent expression of inducible nitric oxide synthase and neuronal apoptosis. J. Neurosci. 21, 1179–1188 (2001)

    CAS  Article  PubMed  Google Scholar 

  12. 12

    Qin, S. et al. System Xc- and apolipoprotein E expressed by microglia have opposite effects on the neurotoxicity of amyloid-β peptide 1–40. J. Neurosci. 26, 3345–3356 (2006)

    CAS  Article  PubMed  Google Scholar 

  13. 13

    Schenk, D. et al. Immunization with amyloid-β attenuates Alzheimer-disease-like pathology in the PDAPP mouse. Nature 400, 173–177 (1999)

    CAS  Article  ADS  PubMed  Google Scholar 

  14. 14

    Nagele, R. G., Wegiel, J., Venkataraman, V., Imaki, H. & Wang, K. C. Contribution of glial cells to the development of amyloid plaques in Alzheimer’s disease. Neurobiol. Aging 25, 663–674 (2004)

    CAS  Article  PubMed  Google Scholar 

  15. 15

    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)

    CAS  Article  PubMed  Google Scholar 

  16. 16

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

    CAS  Article  ADS  PubMed  Google Scholar 

  17. 17

    Jung, S. et al. Analysis of fractalkine receptor CX(3)CR1 function by targeted deletion and green fluorescent protein reporter gene insertion. Mol. Cell. Biol. 20, 4106–4114 (2000)

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  18. 18

    Bacskai, B. J. et al. Imaging of amyloid-β deposits in brains of living mice permits direct observation of clearance of plaques with immunotherapy. Nature Med. 7, 369–372 (2001)

    CAS  Article  PubMed  Google Scholar 

  19. 19

    Geula, C. et al. Aging renders the brain vulnerable to amyloid β-protein neurotoxicity. Nature Med. 4, 827–831 (1998)

    CAS  Article  PubMed  Google Scholar 

  20. 20

    Knowles, R. B. et al. Plaque-induced neurite abnormalities: implications for disruption of neural networks in Alzheimer’s disease. Proc. Natl Acad. Sci. USA 96, 5274–5279 (1999)

    CAS  Article  ADS  PubMed  Google Scholar 

  21. 21

    Le, R. et al. Plaque-induced abnormalities in neurite geometry in transgenic models of Alzheimer disease: implications for neural system disruption. J. Neuropathol. Exp. Neurol. 60, 753–758 (2001)

    CAS  Article  PubMed  Google Scholar 

  22. 22

    Jarrett, J. T. & Lansbury, P. T. Seeding ‘one-dimensional crystallization’ of amyloid: a pathogenic mechanism in Alzheimer’s disease and scrapie? Cell 73, 1055–1058 (1993)

    CAS  Article  PubMed  Google Scholar 

  23. 23

    Meyer-Luehmann, M. et al. Exogenous induction of cerebral β-amyloidogenesis is governed by agent and host. Science 313, 1781–1784 (2006)

    CAS  Article  ADS  PubMed  Google Scholar 

  24. 24

    Walsh, D. M. et al. Naturally secreted oligomers of amyloid-β protein potently inhibit hippocampal long-term potentiation in vivo . Nature 416, 535–539 (2002)

    CAS  Article  ADS  PubMed  Google Scholar 

  25. 25

    Lesne, S. et al. A specific amyloid-β protein assembly in the brain impairs memory. Nature 440, 352–357 (2006)

    CAS  Article  ADS  PubMed  Google Scholar 

  26. 26

    Spires, T. L. et al. Dendritic spine abnormalities in amyloid precursor protein transgenic mice demonstrated by gene transfer and intravital multiphoton microscopy. J. Neurosci. 25, 7278–7287 (2005)

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  27. 27

    Klunk, W. E. et al. Imaging Aβ plaques in living transgenic mice with multiphoton microscopy and methoxy-X04, a systemically administered Congo red derivative. J. Neuropathol. Exp. Neurol. 61, 797–805 (2002)

    CAS  Article  PubMed  Google Scholar 

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Acknowledgements

This work was supported by a grant from the National Institutes of Health and an award from the Alzheimer’s Association. We also thank S. Freeman (Harvard Medical School, Boston) for technical advice and W. E. Klunk (University of Pittsburgh) for the gift of methoxy-XO4.

Author Contributions M.M.-L. and B.T.H. designed the study; M.M.-L., T.L.S.-J., C.P., M.G.-A., A.de C. and A.R. performed experiments; J.K.-T. and D.M.H. provided mice; M.M.-L. and B.T.H. wrote the manuscript; B.J.B. gave technical support and conceptual advice; B.T.H. supervised the study.

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Correspondence to Bradley T. Hyman.

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Meyer-Luehmann, M., Spires-Jones, T., Prada, C. et al. Rapid appearance and local toxicity of amyloid-β plaques in a mouse model of Alzheimer’s disease. Nature 451, 720–724 (2008). https://doi.org/10.1038/nature06616

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