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Transmission of cerebral amyloid pathology by peripheral administration of misfolded Aβ aggregates

Molecular Psychiatry volume 26, pages 5690–5701 (2021)Cite this article

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Abstract

Previous reports showed that brain Aβ amyloidosis can be induced in animal models by exogenous administration of pre-formed aggregates. To date, only intra-peritoneal and intra-venous administrations are described as effective means to peripherally accelerate brain Aβ amyloidosis by seeding. Here, we show that cerebral accumulation of Aβ can be accelerated after exposing mouse models of Alzheimer’s disease (AD) to Aβ seeds by different peripheral routes of administration, including intra-peritoneal and intra-muscular. Interestingly, animals receiving drops of brain homogenate laden with Aβ seeds in the eyes were efficiently induced. On the contrary, oral administration of large quantities of brain extracts from aged transgenic mice and AD patients did not have any effect in brain pathology. Importantly, pathological induction by peripheral administration of Aβ seeds generated a large proportion of aggregates in blood vessels, suggesting vascular transport. This information highlights the role of peripheral tissues and body fluids in AD-related pathological changes.

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Fig. 1: Tg2576 mice challenged with Aβ seeds by different routes developed accelerated brain amyloidosis.
Fig. 2: Evaluation of insoluble Aβ42 levels in Tg2576 mice receiving biologically active seeds by peripheral routes.
Fig. 3: Comparison of Aβ burden between seeded and untreated Tg2576 sacrificed at different time points.
Fig. 4: Seeded Aβ deposits in the brain of Tg2576 mice are highly associated with blood vessels.
Fig. 5: Regional profile of Aβ deposition in exogenously induced mice compared with untreated aged animals.
Fig. 6: Morphological and staining differences in Aβ deposits induced by different routes of administration.

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Acknowledgements

The authors would like to thank Mrs. Andrea Flores-Ramirez for animal care and genotyping. This work was supported by grants from the NIH (RF1 AG061069 to CS and RF1 AG059321 to CS and RM), the Alzheimer’s Association (MNIRGD-12-243075 and NIRGD-15-363554 to RM, NIRP-12-257323 to IM-G and AARG-591107 to CDA), grants from ANID (ANID/FONDEF ID20I10152 and ANID/FONDECYT 1210622) to CDA, a grant from The Mitchell Foundation (to CS), and a Ramon y Cajal Program (RYC-2017-21879) to IM-G. We also acknowledge the use of tissues procured by the National Disease Research Interchange (NDRI) with support from NIH grant U42OD11158.

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  1. These authors contributed equally: Rodrigo Morales, Javiera Bravo-Alegria

Authors and Affiliations

  1. Mitchell Center for Alzheimer’s Disease and Related Brain Disorders, Department of Neurology, The University of Texas Health Science Center at Houston, Houston, TX, USA

    Rodrigo Morales, Javiera Bravo-Alegria, Ines Moreno-Gonzalez, Claudia Duran-Aniotz, Nazaret Gamez, George Edwards III & Claudio Soto

  2. Centro integrativo de biología y química aplicada (CIBQA), Universidad Bernardo O’Higgins, Santiago, Chile

    Rodrigo Morales & Ines Moreno-Gonzalez

  3. Universidad de los Andes, Facultad de Medicina, Santiago, Chile

    Javiera Bravo-Alegria, Claudia Duran-Aniotz & Claudio Soto

  4. Department of Cell Biology, Genetic and Physiology, Faculty of Sciences, University of Malaga-Instituto de Investigacion Biomedica-IBIMA, Networking Research Center on Neurodegenerative Diseases (CIBERNED), University of Malaga, Malaga, Spain

    Ines Moreno-Gonzalez & Nazaret Gamez

  5. Center for Social and Cognitive Neuroscience (CSCN), School of Psychology, Universidad Adolfo Ibáñez, Santiago, Chile

    Claudia Duran-Aniotz

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Contributions

RM and CS designed the experiments. RM, JB-A, IM-G, CD-A, NG and GEIII performed the experimental work. RM, JB-A, IM-G and CS analyzed the data. RM wrote the manuscript. All authors reviewed and approved the final version of this article.

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Correspondence to Rodrigo Morales or Claudio Soto.

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Morales, R., Bravo-Alegria, J., Moreno-Gonzalez, I. et al. Transmission of cerebral amyloid pathology by peripheral administration of misfolded Aβ aggregates. Mol Psychiatry 26, 5690–5701 (2021). https://doi.org/10.1038/s41380-021-01150-w

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