Summary: Amyloid-beta proteins created in the liver are carried in the blood by lipoproteins to the brain. This results in neurodegeneration, brain atrophy, and inflammation, which are common features of Alzheimer’s disease.
Amyloid protein made in the liver can cause neurodegeneration in the brain, according to a new study in the open-access journal PLOS Biology, by John Mamo of Curtin University in Bentley, Australia, and colleagues. Since the protein is thought to be a key contributor to development of Alzheimer’s disease (AD), the results suggest that the liver may play an important role in the onset or progression of the disease.
Deposits of amyloid-beta (A-beta) in the brain are one of the pathological hallmarks of AD and are implicated in neurodegeneration in both human patients and animal models of the disease. But A-beta is also present in periphereral organs, and blood levels of A-beta correlate with cerebral amyloid burden and cognitive decline, raising the possibility that peripherally produced a-beta may contribute to the disease.
Testing that hypothesis has been difficult, since the brain also produces A-beta, and distinguishing protein from the two sources is challenging.
In the current study, the authors surmounted that challenge by developing a mouse that produces human a-beta only in liver cells. They showed that the protein was carried in the blood by triglyceride-rich lipoproteins, just as it is in humans, and passed from the periphery into the brain.
They found that mice developed neurodegeneration and brain atrophy, which was accompanied by neurovascular inflammation and dysfunction of cerebral capillaries, both commonly observed with Alzheimer’s disease. Affected mice performed poorly on a learning test that depends on function of the hippocampus, the brain structure that is essential for the formation of new memories.
The findings from this study indicate that peripherally derived A-beta has the ability to cause neurodegeneration and suggest that A-beta made in the liver is a potential contributor to human disease. If that contribution is significant, the findings may have major implications for understanding Alzheimer’s disease.
To date, most models of the disease have focused on brain overproduction of A-beta, which mimics the rare genetic cases of human Alzheimer’s. But for the vast majority of AD cases, overproduction of A-beta in the brain is not thought to be central to the disease etiology. Instead, lifestyle factors may play a more important role, including a high-fat diet, which might accelerate liver production of A-beta.
The effects of peripheral A-beta on brain capillaries may be critical in the disease process, Mamo adds. “While further studies are now needed, this finding shows the abundance of these toxic protein deposits in the blood could potentially be addressed through a person’s diet and some drugs that could specifically target lipoprotein amyloid, therefore reducing their risk or slowing the progression of Alzheimer’s disease.”
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.
About this Alzheimer’s disease research news
Author: Claire Turner
Contact: Claire Turner – PLOS
Image: The image is credited to John Charles Louis Mamo, Lam V et al., 2021, PLOS Biology
Original Research: Open access.
“Synthesis of human amyloid restricted to liver results in an Alzheimer disease–like neurodegenerative phenotype” by Lam V, Takechi R, Hackett MJ, Francis R, Bynevelt M, Celliers LM, et al. PLOS Biology
Synthesis of human amyloid restricted to liver results in an Alzheimer disease–like neurodegenerative phenotype
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.