Alzheimer's New Possible Cure

In the summer of 2024, I flew halfway across the world to the country I could have grown up in. Summer in South Korea was comparably less unbearable to Austin, Texas's scorching heat and more like a paradise: aesthetic stores on every street, filled with beautiful pastries and photo spots. That paradise ended one night on a brightly lit street in Seoul. My family passed by neon lights advertising karaoke rooms and restaurants and climbed up a few stories to a small, quiet nursing home, where I saw the remnants of a person suffering from Parkinson's.

Parkinson's is characterized by a degrading nervous system and symptoms start slowly, and most often, in the sign of tremors in the hand, foot, or jaw. The early stages of Parkinson's distinguished by a face showing little expression, arms that do not swing when walking, and slurring speech, and symptoms worsen as time goes on.

Alzheimer's disease differs in many ways to Parkinson's. It is a common form of dementia, caused by a buildup of proteins in the brain, causing brain cells to die and the brain shrinks. Common symptoms in the early stage of the disease include forgetting events and the progress of Alzheimer's leads to affecting one's ability to perform everyday tasks.

However, the rise of nanotechnology (briefly mentioned here) has opened doors to many previously impossible tasks - from making additives to fabrics to prevent wrinkling or staining and transistors smaller than one nanometer to being able to treat blocked arteries. Now, there is a possibility of creating a cure for Alzheimer's, using the power of nanotechnology.

Huang et. al, in a research article published in June 2023, explores nanoparticles that could act as neuroinflammation regulators against Alzheimer's.

Alzheimer's disease (AD) is characterized by the inflammatory responses, which is seen in oxidative stress. Oxidative stress occurs when there is an imbalance between free radicals and antioxidants. Free radicals can be described as a molecule that looks for a partner: they are made up to an odd number of electrons. Antioxidants, a well known term but less known for what they actually do, work to prevent or delay cell damage. They also have an uneven number of electrons and thus are perfect "partners" for free radicals. Therefore, when there is an imbalance, free radicals begin to harm the body's tissues. This plays a role in many conditions: cancer, cardiovascular disease, kidney diseases, etc.

AD is also characterized by microglia overactivation. Microglia activation occurs in response to damage in neurons. Overactivation is when the brain's immune cells (which are activated when neurons are damaged) are excessively activated, leading to a strong inflammatory response. Brain immune cells, when activated, release neurotoxic damage because they may be activated when it is not needed or in response to chronic inflammation. The neurotoxic damage damages neurons. This becomes the opposite of what brain immune cells are built to do - remove damaged cells and maintain a healthy environment.

The overactivation of brain immune cells is seen in both Parkinson's and Huntington's. Huntington's disease is an inherited disease that causes nerve cells to degenerate, leading to having trouble thinking and moving. This over activation can be caused by genetics, the environment, and autoimmune reactions (the body attacks itself).

The impairment of neurons exacerbates Aβ collection in the body. Aβ stands for metal-ion triggered amyloid-beta. An increase in metal ions (Sodium, Potassium, Calcium, etc.) is associated with oxidative stress. Amyloid-beta (Aβ ) is a byproduct of normal brain functions. In healthy brains, Aβ is broken down and cleared out. In AD, it accumulates.

To resolve this problem, Huang et. al constructed multifunctional melanin-like metal ion chelators. Chelators work by chelating, or, attaching to metal ions, and this helps them remove toxic materials from the body (toxic materials taken out via urine). Melanin has a natural chelating ability so the nanoparticle was built to imitate its functions. For instance, melanin in the skin attaches to metal ions in order to protect the skin from oxidative stress.

The team, in conclusion, made neuroinflammation regulators (PDA@K), which have a role that sounds exactly like its name - they prevent inflammation in the neurons (brain nerves). PDA is a combination of the metal ions chelators and the neuroinflammation regulator.

Fig 1. Schematic diagram of the strategy (link)

The image above illustrates the process of curing Alzheimer's (although not entirely). Initially, RAGE (a transporter for Aβ), allows PDA (remember, the inflammation regulators!!) to enter where the BBB (Blood-Brain Barrier) is diseased by attaching to Aβ in order to hitch a ride into the brain.

The barrier works to regulate the entrance of molecules from the blood to the brain. It can become diseased through infection, inflammation, or neurological diseases (strokes, etc.) When diseased, it cannot properly regulate the entrance of things so Aβ is able to accumulate in unhealthy amounts.

Second, PDA assists in metal ion chelation. Third, PDA binds to healthy neurons and carries out ROS scavenging. ROS scavenging is the process of removing byproducts of cell metabolism (creating energy). If the byproducts accumulate, it can also cause oxidative stress.

Finally, is microglia normalization. Remember microglias? Normalization returns microglias to their normal state, which helps with stopping its over activation.

In conclusion, the engineered PDA@K effectively stopped Aβ accumulation and reduced neuroinflammation. When mice were put through 3 week of treatment, spatial learning (understanding and remembering) and memory was rescued.