Amyloid protein made in the liver may cause neurodegeneration in the brain, Australian research shows.
And since the protein is thought to be a key contributor to development of Alzheimer’s disease, the findings could create new opportunities for prevention of dementia through diet, lifestyle and lipid modulating drugs, according to a team at Curtin University in Perth, WA.
Their study used mice genetically-engineered to synthesise human amyloid beta (Aß) only in liver to show that it can cause neurodegeneration, brain atrophy, neurovascular inflammation and cerebral capillary dysfunction.
Additionally, the liver Aß affected animals performed poorly on a passive avoidance test, suggesting hippocampal-dependent learning impairment, the authors reported in PLOS Biology.
The findings indicate that peripherally-derived amyloid-beta has the ability to cause neurodegeneration and can be a potential contributor to human disease, they said.
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 amyloid-beta, which mimics the rare genetic cases of human Alzheimer’s, but is not thought to be the central cause in most cases.
While researchers have considered the possible contribution of peripherally-made amyloid beta, differentiating between brain and peripherally-derived peptide has been challenging.
Results from animals that only produced amyloid-beta in the liver might mean lifestyle factors could play an important role in Alzheimer’s disease, the authors said.
For example, a high-fat diet, might accelerate liver production of amyloid-beta.
“Patients with a propensity for exaggerated biosynthesis of [triglyceride-rich lipoproteins], or reduced clearance of triglyceride-rich lipoproteins; putative synergistic effects with dietary fats, or with apo E genotype, will be critical for considering potential AD risk reduction strategies,” the authors wrote
“The latter may include lifestyle and particularly dietary interventions for prevention, or reconsideration of lipid-modulating drugs in positively modulating lipoprotein-Aβ metabolism. 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.”
Study co-author Professor John Malmo said the effects of peripheral amyloid-beta on brain capillaries may be critical in the disease process.
“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,” he said in a media statement.