A New Way of Thinking About Alzheimer’s Disease

            Alzheimer’s disease is a devastating neurodegenerative disorder that causes dementia and irreversible cell death leading to cognitive impairment and can result in death. It is thought that over 5 million Americans are affected by this disease, however, there seems to be no effective treatment in site, how could this be? Perhaps it is because the way in which AD is thought about traditionally is not helping this cause. It is commonly thought that AD disease is directly caused by the buildup of plaques and tangles, and though this is definitely an important characteristic of this disease it is not the root of the problem. Every individual has a natural build up of these molecules as they age but only some will develop AD. Recent information points toward a more direct cause of AD involving synaptic degeneration caused by excess intracellular calcium.

A recent lecture given at Loyola University Chicago by Dr. Beth Stutzmann explores the early molecular mechanisms that lead to synaptic degeneration and the reasons why this is a more effective way of looking at AD. In her talk Dr. Stutzmann lists clinical trials that focused on the buildup of plaques and tangles, all of which have failed. She then goes on to show her research, which looks more at the early mechanisms of AD and how this affects normal synaptic function. She explains that the endoplasmic reticulum, which stores excess Ca²⁺, has an ion channel: ryanodine receptor (RYR) through which calcium ions can escape. If there is a higher number of these channels in the membrane of the ER there is an abnormally high levels of intracellular Ca²⁺. This is what leads to synaptic degeneration because the synapses become overly stimulated and atrophy. Moreover, these increased levels of calcium make it easier for tau to be hyper-phosphorylated in the cell, which leads to the destabilization of microtubules, another hallmark of AD. Clearly, AD is more complicated than previously expected and the root of the disease could come from extremely high levels of Ca²⁺ that cause the damage of the cell and degeneration do synapses.

In accordance with this, a new article published earlier this year by The Scientific American details the failure of even more clinical trials that attempt to target the buildup of plaques in the brains of AD patients. The article refers to one trial run by the company Merck & Co, which was testing its drug verubecestat given to individuals who have mild to moderate AD. The clinical trial had to be stopped as it was determined that it would not result in a positive treatment. verubecestat is a drug that belongs to a group of drugs called BACE1, which target an enzyme thought to be involved in the formation of the amyloid protein, which turn into plaques. In addition, another company that experienced similar results was Eli Lilly and Co, which used drugs like solanezumab, this drug is similar to verubecestat because it targets plaque build up but does so through a different mechanism. Solanezumab failed to reduce cognitive decline in patients with very mild symptoms.

It is clear that new approaches to AD must be explored in order to help develop new and effective treatments. Perhaps targeting the degradation of synapses could prove to be the key to treating AD.

 Citation:

Reutors Staff. “Alzheimer's Drug Fails in Another Crushing Disappointment.” Scientific American, 15 Feb. 2017, www.scientificamerican.com/article/alzheimer-rsquo-s-drug-fails-in-another-crushing-disappointment/