Sribas Chowdhury, Adamas University, Kolkata
Neurodegenerative diseases like Alzheimer’s are some of the most complicated diseases existing amongst modern humankind. These diseases are often complicated to understand. And since their causative agents are unknown in 80% of cases, their treatment is even more challenging. Primarily, the reasons associated with AD were mainly centered around the brain. However recently, a group of researchers at the University of Australia found a link between liver and Alzheimer’s disease.
Alzheimer’s disease
Alzheimer’sdisease (AD) is a slowly progressing neurologic disorder. In this, the brain shrinks, and the brain cells slowly die. The person suffering from Alzheimer’s starts with forgetting little things and eventually it progresses into complete loss of memory. In extreme cases, the person doesn’t even remember how his/her face. In the US, approximately 58 million people suffer from it and most of them are over 75 years old. Because the causative agents of this disease are not specifically known, there is no cure for it. Certain drugs are given to slow down the progression of memory loss although there is no certainty. The highlighted study, headed by John Mamo, indicated a link between AD and liver cells (hepatocytes ) via a protein.
Linkage
The protein in question is amyloid-beta (Aß), an aggregate of 36-43 amino acids. Studies have shown that the metabolism of this protein poses a risk for Alzheimer’s disease. This protein is hence, treated as a pathological indicator of AD. Around 90% of this protein is found in the blood in the form of apo-lipoprotein and is produced by peripheral organs. Apo-lipoproteins are proteins that bind to fats and cholesterol and transport them via blood. Since the liver is the primary organ of cholesterol production, it was suspected that Alzheimer’s disease may have a connection with hepatocytes (liver cells). Interestingly, amyloid-beta was mainly associated with triglyceride-rich lipoprotein (TRL), which is derived from hepatocytes. This further solidified the speculation that peripherally produced amyloid-beta might have a role in Alzheimer’s disease which was the focus of this study.
Methodology of study
For the study, the scientists genetically modified a group of mice to produce amyloid-beta only from hepatocytes. This strain of transgenic mice was called the hepatocyte-specific human amyloid (HSHA) strain. In HSHA, the protein was associated with TRLs and passed from peripheral organs to the brain via blood. Then, at the age of 4,6,8, 12, and 18 months, they were killed through cardiac puncture. Their brain tissues were collected and studied via spectroscopic lipid imaging.
Observations
The HSHA strain was observed to have developed neurodegeneration (loss of function of neurons) and brain atrophy (loss of neural connection). Their performance on a learning test based on the function of the hippocampus was poor, indicating loss of neural pathways. Furthermore, these mice showed inflammation of vascular tissues in the brain. Their cerebral capillaries were also found to be dysfunctional. Both of these symptoms are clinically observed with Alzheimer’s disease, hence validating the speculation.
Should we be worried?
The study definitely opened new possibilities for understanding neurodegenerative disorders. It indicated that peripherally derived amyloid-beta has the potential to cause neurodegeneration, thereby proving that liver cells may have a role to play in Alzheimer’s disease.
However, the lead researcher John Mamo still not convinced that overproduction of amyloid-beta by peripheral organs is the primary cause of AD. He attributed it more to other causes like genetic makeup, lifestyle, and type of diet. While it is a matter of worry, Mamo believes that their production can be controlled by proper diet and certain drugs. As per future prospects, further studies are needed to gain more insights to fully understand and treat such complex disorders.
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Reference:
- Lam, V., Takechi, R., Hackett, M. J., Francis, R., Bynevelt, M., Celliers, L. M., Nesbit, M., Mamsa, S., Arfuso, F., Das, S., Koentgen, F., Hagan, M., Codd, L., Richardson, K., O’Mara, B., Scharli, R. K., Morandeau, L., Gauntlett, J., Leatherday, C., … Mamo, J. C. L. (2021). Synthesis of human amyloid restricted to liver results in an Alzheimer disease–like neurodegenerative phenotype. PLOS Biology, 19(9), e3001358. https://doi.org/10.1371/journal.pbio.3001358
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