New findings show that amyloid protein made in the liver can cause neurodegeneration in the brain.
Accumulation of the protein amyloid-beta (A-beta)in parts of the brain is a hallmark of Alzheimer’s disease (AD) and now it seems like this protein can be made in the liver, from where it can reach the brain and cause neurodegeneration. The findings of this new study, led by Dr John Mamo, from Curtin University in Perth, suggest that the liver may play a more important role in the onset or progression of AD.
Previous studies have shown positive correlations between levels of amyloid beta in the blood and cerebral amyloid burden and cognitive decline in patients with Alzheimer disease. However, it has not been clearly established where circulating A-beta originates nor a causal relationship has been clearly defined, linking circulating A-beta with the development of AD, as the brain also produced A-beta.
To address these issues, researchers designed a new animal model that produces human A-beta only in liver cells. Their engineered mice produced A-beta in the liver, which was then carried in the blood triglyceride-rich lipoproteins, just as it is in humans, and entered the brain.
The mice then developed neurodegeneration and brain atrophy, accompanied by neurovascular inflammation and dysfunction of cerebral capillaries, all common ailments caused by Alzheimer’s disease. The affected mice also performed poorly on learning tests that evaluated the function of the hippocampus, a part of the brain involved with the formation of new memories.
“This study provides compelling evidence that amyloid produced in the liver may contribute to the development and progression of Alzheimer’s brain pathology. It’s an exciting result and adds to the growing literature that the origins, or at least drivers, of some neurodegenerative diseases may lie outside of the brain,” said Dr Axel Montagne, Group Leader at the UK Dementia Research Institute, University of Edinburgh.
The findings of this study suggest that A-beta produced in the liver has the capacity of causing neurodegeneration and may be a potential contributor in the human version of the disease. If these findings hold in humans, there are important implications for how AD is managed and treated.
“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,” Dr Mamo said in a press release.
However, not everyone agrees with this view on potential lifestyle changes. “I’m afraid I don’t really agree with the author’s suggestion that reducing lipid levels in the blood, for example by making changes to diet, could reduce A-beta and reduce the risk of Alzheimer’s disease. I think if there was a strong connection between lipid levels and Alzheimer’s disease risk then we would already know about it from previous studies,” Prof David Curtis, Honorary Professor, at University College London Genetics Institute. “I think the main value of this research will be to make it easier to develop new effective treatments for Alzheimer’s disease which target the A-beta levels directly,” he added.
The authors conclude with a word of advice on how to move forward. “Indeed, a clinical trial exploring the putative efficacy of probucol on cognitive performance in patients with mild cognitive impairment/early AD has been proposed based on the findings of potent suppression of Aβ biosynthesis and lipoprotein-associated secretion in preclinical models,” the authors said in their report.