Researchers use worms with Alzheimer’s to determine if changes in metabolism cause Alzheimer’s disease.
Alzheimer’s disease is a mental disorder that is characterized by a loss of memory and decline in cognitive function. The reason for this decline in mental function is the accumulation of protein aggregates called amyloid-beta (Aβ) peptides, these protein clumps are insoluble and form amyloid plaques in the brain. Another characteristic of Alzheimer’s disease is the presence of neurofibrillary tangles which are caused by the presence of tau proteins that have too many phosphates which cause these proteins to stick together. Scientists are still unsure of what causes these irregularities in protein formation. There is evidence to suggest that changes in the way cells make energy may cause the neuronal degradation seen in Alzheimer’s disease.
Oxidative stress damages cells
When a cell processes glucose to form energy, it uses oxygen. This process is known as oxidative phosphorylation and is carried out in the mitochondria of cells. During this process, the cell generates reactive oxygen species (a group of highly reactive chemicals that contain oxygen). Oxidative stress occurs when too many reactive oxygen species are produced. These molecules then react with proteins, lipids and nucleic acids which can cause damage to the cell. Aging cells are affected by increasing amounts of oxidative stress and are prone to mitochondrial and protein dysfunction. The brains of patients with Alzheimer’s disease show extensive damage due to oxidative stress and this may play a role in disease progression. How oxidative stress links to amyloid formation and the formation of neurofibrillary tangles is not well understood.
Can worms help us understand the cause of Alzheimer’s disease?
In a recent study published in eLife, researchers in Singapore wanted to know if metabolic shifts in the mitochondria contributed to the early stages of Alzheimer’s disease. The researchers decided to use worms to model the disease. Specifically, the team used, Caenorhabditis elegans because these animals have a short life span, making it easier to follow disease progression. They also have a well-characterized genome and can be genetically engineered with relative ease. The researchers used genetic engineering to make a worm that had Alzheimer’s disease. They inserted a gene into the neural cells of the worm that caused these cells to make small amounts of human Aβ peptides. These transgenic worms have physical traits such as neuromuscular and behavioural defects that get worse with age and reduction in life span. These worms suffer from poor energy metabolism and the scientists wanted to understand the difference between worms with Alzheimer’s disease compared to the control group. They investigated the differences in intermediary metabolites involved with energy metabolism and found that the worms with Alzheimer’s had lower total amounts of amino acids. The team went on to analyses the amino acid profile of the worms and found that the percentage of amino acids forming alpha-Ketoglutarate (aKG) was significantly increased. The researchers went on to look at what metabolic pathways the amino acids were involved in. They used computational analysis of metabolic data and transcriptomics to map the interactions in young worms. This analysis showed several reactions involving aKG and this motivated the researchers to further investigate aKG as a factor that may be involved in metabolic defects seen in Alzheimer’s disease. The team went on to show there was a significant reduction in the enzyme activity of aKG dehydrogenase. This protein has an essential role within the Krebs cycle, which is responsible for energy production within the cell.
Does oxidative stress cause mitochondrial dysfunction?
The scientists then went on to prevent aKG dehydrogenase from being made in healthy worms to investigate if this affected metabolism. They found when the enzyme is not made there is a reduction in respiration, and preventing aKG dehydrogenase production recapitulated the same key metabolic deficits seen in the worms engineered to have Alzheimer’s. The group wanted to know if reactive oxygen species could cause the mitochondrial dysfunction they observed in the worms. They examined the protein carbonyl content in the worms as this is a marker for oxidative stress. The team found that there was an increase in the number of mitochondrial proteins with carbonylation in young worms engineered to have Alzheimer’s. This suggests that oxidative stress within the mitochondria may be an early pathogenic event in Alzheimer’s disease.
Is metformin a potential therapy for Alzheimer’s?
The scientists were interested to know what effects metformin would have on the worms. Metformin is an anti-diabetic drug that can increase Krebs cycle metabolism. The researchers showed the when worms with Alzheimer’s were treated with this drug they were able to increase the lifespan of the worms. The team wanted to know what metabolic substrates were responsible for this effect so they performed a metabolic analysis. They found that worms treated with metformin had an abundance of amino acids involved in the Krebs cycle. They also showed that metformin can improve energy substrate availability within the mitochondria which may help prevent Aβ peptide toxicity. The scientists were able to show the worms with human Aβ peptides had higher amounts of insoluble proteins compared to controls. When these worms were treated with metformin however there was no significant difference in the amount of insoluble proteins between treated and untreated groups.
This research appears to support the idea the metabolic dysfunction occurs long before amyloid formation in Alzheimer’s disease progression. There are however a few constraints that need further consideration. The research team did not demonstrate the mechanism for how metabolic or alpha-Ketoglutarate dysfunction may contribute to tau or amyloid plaque formation. They were not able to show that oxidative stress caused AB aggregation only that it may occur at early stages of the disease and may negatively impact disease progression. Although metformin treatment in worms was able to extend the life span of the worms the team was unable to show a reduction in the amount of Aβ aggregates.
Written by Tarryn Bourhill MSc, PhD candidate
References:
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Swerdlow, R. H. Mitochondria and cell bioenergetics: increasingly recognized components and a possible etiologic cause of Alzheimer’s disease. Antioxidants & redox signaling 16, 1434-1455 (2012).
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Müller, W. E., Eckert, A., Kurz, C., Eckert, G. P. & Leuner, K. Mitochondrial dysfunction: common final pathway in brain aging and Alzheimer’s disease—therapeutic aspects. Molecular neurobiology 41, 159-171 (2010).
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Benedict, C. & Grillo, C. A. Insulin resistance as a therapeutic target in the treatment of Alzheimer’s disease: a state-of-the-art review. Frontiers in neuroscience 12, 215 (2018).
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Teo, E. et al. Metabolic stress is a primary pathogenic event in transgenic Caenorhabditis elegans expressing neuronal human amyloid-β. BioRxiv, 708537 (2019).
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