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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 OMara Rainer K. Scharli Laurence Morandeau Jonathan Gauntlett Christopher Leatherday Jan Boucek John C. L. Mamo 《PLoS biology》2021,19(9)
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.It has been suggested that peripheral metabolism of amyloid-beta is associated with risk for Alzheimer’s disease. This study reveals that the expression of human amyloid exclusively in the liver induces Alzheimer’s disease-like pathologies in mice, potentially indicating a completely novel pathway of Alzheimer’s disease aetiology and therapies. 相似文献
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