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Imaging of amyloid-β deposits in brains of living mice permits direct observation of clearance of plaques with immunotherapy

Nature Medicine volume 7, pages 369–372 (2001)Cite this article

Alzheimer disease (AD) can be diagnosed with certainty only post-mortem, by histologically demonstrating insoluble aggregates of amyloid-β peptide, called senile plaques1,2,3,4. Direct imaging of these lesions in the living brain would revolutionize early diagnosis of AD. Such imaging would also provide a powerful approach to monitor effects of putative anti-amyloid-β agents. However, the plaques are far too small to detect by conventional imaging techniques. The goal of this study was to develop novel imaging approaches, using in vivo multiphoton microscopy, to image senile plaques in PDAPP transgenic mice, which express a mutant human amyloid-β precursor protein and accumulate amyloid-β deposits5,6. We developed two robust methods: in vivo histology using the fluorescent histochemical dye thioflavine S, and in vivo immunofluorescence using labeled antibodies specific for amyloid-β. Immunization with amyloid-β peptide has been shown to prevent plaques in PDAPP mice7. We used our imaging techniques to test the hypothesis that existing plaques can be cleared by immunotherapy.

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Figure 1: Imaging of amyloid-β deposits in the live mouse.
Figure 2: Clearance of dense-core amyloid-β deposits after immunotherapy.
Figure 3: In vivo imaging of amyloid-β deposits in 20-month-old homozygous PDAPP mice.
Figure 4: Histological analysis of imaged brains from 20-month-old homozygous PDAPP mice using biotinylated antibody 3D6 shows an extraordinarily high level of amyloid-β deposits throughout the cortex and hippocampal formation.
Figure 5: Marked local microglial activation, as assessed with biotin-labeled tomato lectin, occurs 3 days after the skull preparation and imaging.
Figure 6: Confocal thin optical sections (0.2 μm) were reconstructed to illustrate the intimate relationship of microglia with remaining amyloid-β three days after treatment with 10D5-fluorescein.

References

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

    Article  CAS  Google Scholar 

  2. 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).

    Article  CAS  Google Scholar 

  3. Davis, D.G., Schmitt, F.A., Wekstein, D.R. & Markesbery, W.R. Alzheimer neuropathologic alterations in aged cognitively normal subjects. J. Neuropathol. Exp. Neurol. 58, 376–388 (1999).

    Article  CAS  Google Scholar 

  4. Naslund, J. et al. Correlation between elevated levels of amyloid beta-peptide in the brain and cognitive decline. JAMA 283, 1571–1577 (2000).

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  6. Irizarry, M.C. et al. Abeta deposition is associated with neuropil changes, but not with overt neuronal loss in the human amyloid precursor protein V717F (PDAPP) transgenic mouse. J. Neurosci. 17, 7053–7059 (1997).

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  8. Denk, W., Strickler, J.H. & Webb, W.W. Two-photon laser scanning fluorescence microscopy. Science 248, 73–76 (1990).

    Article  CAS  Google Scholar 

  9. Svoboda, K., Denk, W., Kleinfeld, D. & Tank, D.W. In vivo dendritic calcium dynamics in neocortical pyramidal neurons. Nature 385, 161–165 (1997).

    Article  CAS  Google Scholar 

  10. Yang, X. et al. Dynamic mapping at the laminar level of odor-elicited responses in rat olfactory bulb by functional MRI. Proc. Natl. Acad. Sci. USA 95, 7715–7720 (1998).

    Article  CAS  Google Scholar 

  11. Hyman, B.T., Tanzi, R.E., Marzloff, K., Barbour, R. & Schenk, D. Kunitz protease inhibitor-containing amyloid beta protein precursor immunoreactivity in Alzheimer's disease. J. Neuropathol. Exp. Neurol. 51, 76–83 (1992).

    Article  CAS  Google Scholar 

  12. Vigo-Pelfry, C. et al. Elevation of microtubule-associated protein tau in the cerebrospinal fluid of patients with Alzheimer's disease. Neurology 45, 788–793 (1995).

    Article  Google Scholar 

  13. Bard, F. et al. Peripherally administered antibodies against amyloid β-peptide enter the central nervous system and reduce pathology in a mouse model of Alzheimer disease. Nature Med. 6, 916–919 (2000).

    Article  CAS  Google Scholar 

  14. Solomon, B. et al. Monoclonal antibodies inhibit in vitro fibrillar aggregation of the Alzheimer beta-amyloid peptide. Proc. Natl. Acad. Sci. USA 93, 452–455 (1996).

    Article  CAS  Google Scholar 

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Acknowledgements

This work was supported by grants from the National Institute on Aging (AG08487, P01AG15453 and T32GM07753), and support from the Alzheimer Association and the Walters Family Foundation. An unrestricted gift from Elan Pharmaceuticals supported housing costs for the animals.

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Authors and Affiliations

  1. Alzheimer's Disease Research Laboratory, Massachusetts General Hospital, Charlestown, Massachusetts, USA

    Brian J. Bacskai, Stephen T. Kajdasz, Richard H. Christie, Cordelia Carter & Bradley T. Hyman

  2. Elan Pharmaceuticals, South San Francisco, California, USA

    Dora Games, Peter Seubert & Dale Schenk

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  1. Brian J. Bacskai
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Correspondence to Bradley T. Hyman.

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Bacskai, B., Kajdasz, S., Christie, R. et al. Imaging of amyloid-β deposits in brains of living mice permits direct observation of clearance of plaques with immunotherapy. Nat Med 7, 369–372 (2001). https://doi.org/10.1038/85525

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