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Strain brain app12/30/2023 The latter suggests that metabolism of the lipoprotein-Aβ moiety within the neurovascular unit (NVU) might exacerbate inflammatory processes that compromise neurovascular integrity. Consistent with the latter, Matsuzaki and colleagues reported that lipidated-Aβ was found to be toxic to Chinese hamster ovary cells in culture, but not native Aβ, and in cell cultures studies, macrophages were found to have unabated uptake of TRL. Collectively, it is a reasonable proposition that putative extracellular parenchymal retention of TRL-Aβ is likely to be inflammatory and could promote AD onset or progression. Moreover, synergistic effects of TRL-Aβ with exaggerated central nervous system (CNS) synthesis of human Aβ are also suggested by the findings of accelerated amyloidosis in amyloid precursor protein/presenilin 1 (APP/PS1) mice maintained on atherogenic diets. Burgess and colleagues reported that, in TgCRND8 mice, the onset and progression of cerebral amyloidosis was strongly associated with secretion into blood of VLDL-Aβ. Studies in transgenic-human amyloid mice also support a causal association with aberrant metabolism of TRL-Aβ. In contrast, mice fed unsaturated fatty acid–rich diets had no evidence of exaggerated TRL-Aβ secretion and capillary integrity was unremarkable. In wild-type (WT) C57BL/6J mice, a saturated fatty acid (SFA)-enriched diet was found to strongly stimulate biosynthesis and secretion of TRL-Aβ, concomitant with a reduction in cerebral capillary endothelial tight junction proteins, blood-to-brain extravasation of TRL-Aβ, and marked neurovascular inflammation. Direct evidence of a peripheral TRL-Aβ/vascular risk pathway for AD comes from studies in preclinical models, which show that cerebral capillary amyloid-angiopathy, a common early neurovascular pathology of AD, may be a consequence of parenchymal extravasation of TRL-Aβ. Insight into how blood Aβ increases risk for AD comes from findings that in humans, greater than 90% of blood Aβ 1–40 and 97% of the particularly pro-amyloidogenic Aβ 1–42 is associated with plasma lipoproteins, principally the triglyceride-rich lipoproteins (TRLs) of hepatically derived very low-density lipoproteins (VLDLs) and of postprandial chylomicrons. However, presently, the mechanism(s) by which peripheral Aβ metabolism might exacerbate AD risk are not well understood. A causal association is suggested based on the findings that blood measures of Aβ isoforms discriminate with a high degree of accuracy, patients who go on to develop AD decades before onset of disease. Several recent bio-epidemiological studies show that systemic measures of amyloid beta (Aβ) in blood positively correlate with cerebral amyloid burden and cognitive decline in Alzheimer disease (AD). Lipoprotein receptor-related protein MRI, Ionised calcium-binding adaptor molecule 1 IgG, This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.ĭata Availability: All relevant data are within the paper and its Supporting Information files.įunding: This work was funded by the National Health and Medical Research Council (GNT1135590 (RT), GNT1064567 (JM), GNT1156582 (VL) ), and Western Australian Department of Health (RT) (no grant ID, ).The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.Ĭompeting interests: The authors have declared that no competing interests exist.Īustralian Mouse Brain Mapping Consortium apo B,Įukaryote translation elongation factor 2 ES, Received: AugAccepted: JPublished: September 14, 2021Ĭopyright: © 2021 Lam et al. Südhof, Stanford University School of Medicine, UNITED STATES PLoS Biol 19(9):Īcademic Editor: Thomas C. (2021) Synthesis of human amyloid restricted to liver results in an Alzheimer disease–like neurodegenerative phenotype. Citation: Lam V, Takechi R, Hackett MJ, Francis R, Bynevelt M, Celliers LM, et al.
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