Alzheimer’s disease (AD) is a type of dementia that affects the brain and is characterized by the presence of neurofibrillary tangles and amyloid plaques. It is estimated that around 50 million people globally are affected by this disease. AD is considered to be the most expensive medical condition in developed countries due to the long-term support that it requires. Because of the seriousness of the situation, the development of effective prevention and treatment strategies is urgently needed.
Aside from being an essential component of many enzymes, copper is also known to play a role in the development of AD by contributing to the dysregulation of various cellular processes. These include the production of energy, antioxidative defense, and oxidative metabolism. A protein known as an amyloid precursor protein (APP) is a central component of AD pathology as its proteolysis creates Aβ peptides. APP is also copper-regulated. The disturbance of copper metabolism has been known to shift the proteolysis of APP toward the amyloidogenic pathway, which then leads to the initiation and perpetuation of the AD pathologic cascade. Moreover, due to the presence of excess free copper ions in the extracellular space, they can cause oxidative stress and neurotoxic effects in the AD brain. However, there is a copper deficiency in intracellular space of the AD brain. These connections have led to the development of various therapeutic strategies to treat the disease.
Because of these positive effects of copper elimination, some studies have targeted copper chelators as suitable drugs, however, copper chelation therapy results in human clinical trials were discouraging and in the case of AD, there is rather the need for copper redistribution. To address this issue, PhD candidates Kristel Metsla, Sigrid Kirss, Katrina Laks, Gertrud Sildnik, Dr. Mari Palgi, Dr. Teele Palumaa, Associate Professor Vello Tõugu, and Professor Peep Palumaa from the Tallinn University of Technology suggested using another type of molecular tools to regulate the copper metabolism in Alzheimer’s disease. Through a systematic review of the copper(I)-binding properties of potential Alzheimer’s disease drugs, authors identified α-lipoic acid (LA) as a promising substance to treat copper dysregulation. LA is well-tolerated natural compound with an antioxidant properties. They tested its effects on the copper metabolism as it promotes the influx of copper into SH-SY5Y cells through cell culture experiments and the effects of LA dietary supplementation in the AD model in Drosophila melanogaster flies. The original research article is now published in the Journal of Alzheimer’s disease.
The research team used differentiated and non-differentiated SH-SY5Ycells incubated in a culture medium containing copper and LA for 24 h. Cells were then separated from the culture medium and the Cu-63 analysis was performed using an ICP MS instrument. The authors showed that LA promotes the transport of copper ions into cells in a dose-dependent manner. In the case of differentiated “neuron like” SH-Y5Y cells, the effect was more prominent.
Another exciting experiment was conducted by Professor Peep Palumaa and colleagues using the Drosophila melanogaster model of AD. These flies expressing neurodegenerative disease-related genes might be very useful to prove hypotheses in vivo in a fast, effective, and economic manner. They used the nervous system-specific driver line and the responder line carrying the Aβ42 gene with mutation D23N found in AD patients (AD genotype). By crossing these lines it is possible to express Aβ42 D23N peptides in the fruit fly nervous system, which show AD phenotype, reflected in reduced locomotor activity. The authors determined the effects of LA on the locomotor activities of AD flies. After hatching, the adult flies were fed with LA-supplemented food and regular food for 7 days to study the effects of LA on the development of the AD phenotype. The climbing height of each fly was recorded and the average climbing distance was scored. After 7 days, the climbing score of flies that were kept on regular food declined and the climbing score of flies fed food with LA exhibited a lower decline in the climbing score, which suggests that LA prevents the development of AD phenotype in these flies.
In a nutshell, the findings of Professor Peep Palumaa and colleagues support the hypothesis that “disturbed copper metabolism has a crucial role in the pathogenesis of Alzheimer’s disease and α-lipoic acid has the potential to normalize the copper metabolism.” Their preclinical study results, which have to be confirmed in clinical trials, give immense hope to the people suffering from AD and scientists working to elaborate innovative therapeutic strategies for the prevention and treatment of AD.
Metsla K, Kirss S, Laks K, Sildnik G, Palgi M, Palumaa T, Tõugu V, Palumaa P. α-Lipoic Acid Has the Potential to Normalize Copper Metabolism, Which Is Dysregulated in Alzheimer’s Disease. J Alzheimers Dis. 2022;85(2):715-728. doi: 10.3233/JAD-215026. PMID: 34864665.