Alzheimer’s disease is one of the world’s most prevalent brain disorders, being extremely difficult to treat. Alzheimer’s affects millions of people globally, making it one of the most common neurodegenerative diseases. Glutamate, an essential neurotransmitter responsible for regulating functions such as mood and memory, can also encourage the toxic buildup of tau proteins, which are known to contribute to Alzheimer’s and related neurodegenerative diseases.
However, in stem-cell lead research conducted by USC, Stem Cell scientists have revealed a new way to remove toxic tau proteins and lower Alzheimer’s risks. The tau protein, which, when it becomes toxic, can lead to memory loss and cognitive decline. Researchers are now focusing on two main strategies to combat tau buildup: enhancing the body’s ability to clear it and preventing it from becoming harmful in the first place.
Understanding Tau Protein: Its Role in Brain Health and Disease
Tau proteins help stabilize and support the internal structure of brain cells, allowing nutrients to move efficiently and keeping neurons functioning properly. However, in Alzheimer’s and related diseases, tau proteins can malfunction. In the case of tau proteins behaving abnormally, they weaken and break-off from their normal positions. They then begin to clump together and form tangled structures called neurofibrillary tangles. These tangles block communication between neurons (brain cells) leading to memory loss and other cognitive deficit related symptoms.
For years, researchers primarily focused their attention on another protein, beta-amyloid, as the cause of Alzheimer’s. While beta-amyloid plaques are still an addition to the causes of neurodegenerative disease, recent studies show that tau plays a critical role in disease progression. The more tau tangles in the brain, the worse the symptoms of Alzheimer’s become. To address toxic tau build up in the brain, scientists focused on two main approaches, namely clearing toxic tau and preventing tau buildup.
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USC’s Breakthrough: Glutamate and the KCTD20 Gene
A team of USC Stem Cell scientists conducted a study to develop a new approach to tackling these neurodegenerative effects. The USC team made their discovery of counteractive measures to brain degeneration studying “organoids” – basic, lab-grown brain-like structures – and lab mice. When exposed to high levels of glutamate, the organoids and mice showed increased tau buildup, nerve cell death, and signs of Alzheimer’s-like disease.
There have been previous attempts to treat Alzheimer’s with potential drugs designed to block glutamate active, but have had mixed results in clinical trials. These drugs often cause side effects such as memory loss and limited motor function. Instead of targeting glutamate directly, the USC researchers searched for genes that respond to glutamate. They identified a gene called KCTD20. When researchers suppressed this gene in the organoids and mice, glutamate no longer caused tau buildup or brain cell damage.
Further experiments demonstrate that suppressing KCTD20 activates lysosomes, a membrane-bound cell which aids in various cell processes but notably disposing of excess or worn-out cells. These lysosomes engulf the toxic tau proteins and remove them from the organoids’ cells. Jesse Lai, one of the study’s lead authors, stated that they focused on expelling tau-proteins rather than trying to limit glutamate activity.
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The TYK2 Enzyme: A New Target to Stop Tau Damage
Another promising new study published in Nature focuses on an enzyme called tyrosine kinase 2 (TYK2). This enzyme plays a pivotal role in the immune system but also causes excess tau production. In Alzheimer’s, TYK2 adds a chemical tag to the tau proteins, making it harder for the brain to clear away any excess. In a study using Alzheimer’s mice, researchers blocked TYK2 and found that it reduced the amount of toxic tau in the brain.
The brain cells also showed signs of recovery, suggesting that blocking TYK2 could be a new way to treat Alzheimer’s and other neurodegenerative diseases. The good news is that TYK2 inhibitors are already being used in clinical trials for other conditions, such as arthritis and inflammatory bowel disease. However, researchers still need to confirm whether these drugs can reach the brain to target tau effectively.
A New Hope for Alzheimer’s Treatment
While research continues, there are steps to lower Alzheimer’s risk, namely, diet, exercise, and mental engagement. On the medical front, several new treatments are in development. For example, a vaccine called AADvac1 is designed to train the immune system to target harmful tau proteins. Other therapies aim to reduce tau phosphorylation, the process that makes tau toxic. Researchers are focusing on various new methods of treating Alzheimer’s and are making significant strides in understanding and targeting tau protein. The USC study redefines therapeutic priorities by demonstrating that enhancing lysosomal clearance can counteract glutamate-driven tau toxicity. Meanwhile, TYK2 research highlights the importance of preventing tau’s initial transformation into a harmful state. However, it is still inconclusive and more research is needed. As scientists continue to explore these strategies, the future looks brighter for those affected by Alzheimer’s.
Disclaimer: This information is not intended to be a substitute for professional medical advice, diagnosis or treatment and is for information only. Always seek the advice of your physician or another qualified health provider with any questions about your medical condition and/or current medication. Do not disregard professional medical advice or delay seeking advice or treatment because of something you have read here.
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