Synthesis of human amyloid restricted to liver results in an Alzheimer disease-like neurodegenerative phenotype

Virginie Lam; Ryusuke Takechi; Mark J Hackett; Roslyn Francis; Michael Bynevelt; Liesl M Celliers; Michael Nesbit; Somayra Mamsa; Frank Arfuso; Sukanya Das; Frank Koentgen; Maree Hagan; Lincoln Codd; Kirsty Richardson; Brenton O'Mara; Rainer K Scharli; Laurence Morandeau; Jonathan Gauntlett; Christopher Leatherday; Jan Boucek; John C L Mamo

doi:10.1371/journal.pbio.3001358

Synthesis of human amyloid restricted to liver results in an Alzheimer disease-like neurodegenerative phenotype

PLoS Biol. 2021 Sep 14;19(9):e3001358. doi: 10.1371/journal.pbio.3001358. eCollection 2021 Sep.

Authors

Virginie Lam^{1

2}, Ryusuke Takechi^{1

2}, Mark J Hackett^{1

3}, Roslyn Francis^{4

5}, Michael Bynevelt⁶, Liesl M Celliers^{4

7}, Michael Nesbit^{1

2}, Somayra Mamsa¹, Frank Arfuso¹, Sukanya Das¹, Frank Koentgen⁸, Maree Hagan⁸, Lincoln Codd⁹, Kirsty Richardson¹⁰, Brenton O'Mara⁴, Rainer K Scharli^{11

12}, Laurence Morandeau^{11

12}, Jonathan Gauntlett⁸, Christopher Leatherday¹³, Jan Boucek¹³, John C L Mamo^{1

2}

Affiliations

¹ Curtin Health Innovation Research Institute, Faculty of Health Sciences, Curtin University, Bentley, Australia.
² School of Population Health, Faculty of Health Sciences, Curtin University, Bentley, Australia.
³ School of Molecular and Life Sciences, Faculty of Science and Engineering, Curtin University, Bentley, Australia.
⁴ Department of Nuclear Medicine, Sir Charles Gairdner Hospital, Nedlands, Australia.
⁵ School of Medicine and Pharmacology, University of Western Australia, Crawley, Australia.
⁶ Sir Charles Gairdner Hospital, Nedlands, Australia.
⁷ Department of Molecular Imaging and Therapy Service, Fiona Stanley Hospital, Murdoch, Australia.
⁸ Ozgene Pty Ltd, Bentley, Western Australia, Australia.
⁹ Department of Radiology, Sir Charles Gairdner Hospital, Nedlands, Australia.
¹⁰ Laboratory for Cancer Medicine, Harry Perkins Institute of Medical Research, University of Western Australia, Centre for Medical Research, QEII Medical Centre, Australia.
¹¹ Radiopharmaceutical Production and Development Centre (RAPID) PET Laboratories, Sir Charles Gairdner Hospital, Nedlands, Australia.
¹² Physics, University of Western Australia, Nedlands, Australia.
¹³ Health Technology Management Unit, East Metropolitan Health Service, Perth, Australia.

Abstract

Several lines of study suggest that peripheral metabolism of amyloid beta (Aß) is associated with risk for Alzheimer disease (AD). In blood, greater than 90% of Aß is complexed as an apolipoprotein, raising the possibility of a lipoprotein-mediated axis for AD risk. In this study, we report that genetic modification of C57BL/6J mice engineered to synthesise human Aß only in liver (hepatocyte-specific human amyloid (HSHA) strain) has marked neurodegeneration concomitant with capillary dysfunction, parenchymal extravasation of lipoprotein-Aß, and neurovascular inflammation. Moreover, the HSHA mice showed impaired performance in the passive avoidance test, suggesting impairment in hippocampal-dependent learning. Transmission electron microscopy shows marked neurovascular disruption in HSHA mice. This study provides causal evidence of a lipoprotein-Aß /capillary axis for onset and progression of a neurodegenerative process.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Alzheimer Disease*
Amyloid beta-Peptides / biosynthesis*
Amyloid beta-Peptides / genetics
Animals
Blood-Brain Barrier / pathology
Brain / blood supply
Capillaries / pathology
Disease Models, Animal
Hepatocytes / metabolism*
Humans
Inflammation
Learning
Lipoproteins / metabolism
Male
Mice, Transgenic
Nerve Degeneration

Substances

Amyloid beta-Peptides
Lipoproteins

Grants and funding

This work was funded by the National Health and Medical Research Council (GNT1135590 (RT), GNT1064567 (JM), GNT1156582 (VL) https://www.nhmrc.gov.au), and Western Australian Department of Health (RT) (no grant ID, https://ww2.health.wa.gov.au).The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.