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

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2021

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

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

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

Service type: Transgenic mice

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.

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