Alzheimer’s is often described as a disease of progressive plaque formation and of nInduction of apoptosis by the low-affinity NGF receptor” appeared in the journal Science in July 1993 and while the idea of a receptor certainly wasn’t new, the manner in which this receptor functions was completely different. Note – Even though the article was published 2 years after the breakup of the Soviet Union you still can’t read it for free.tangles in the brain, but long before the first plaque forms, a little known cellular process plays a crucial role. That process involves a discovery in 1992 of something called a dependence receptor whose role in Alzheimer’s and other diseases is now fully proven, yet little known outside the high priesthood of research. The discovery, not even 30 years ago, of the first dependence receptor pulled back the curtains on a process with profound implications for our understanding of how Alzheimer’s begins and progresses. That said, you will be forgiven if the title didn’t tip you off to the groundbreaking discovery inside. “
Receptors before 1992
Cells constantly monitor their internal and external environments by deploying receptor proteins. Some receptors float in the cell and send feedback on the state of the cytoplasm while others penetrate the cell membrane like probes to measure the external environment and send signals back to the interior. Biology textbook illustrations make this look as simple as I just made it sound, but the reality is of course crowded and complex. How do you begin to depict such things as the existence of 100,000 mitochondria (MOL) and the army of receptor proteins deployed by a single cell?
We leave out overwhelming detail of cellular function to focus on the process at hand. Sometimes we leave process out of the discussion because it’s not yet understood. I know that sounds crazy in this day and age, but researchers are still discovering not only the existence of proteins, receptors, enzymes, mechanisms and entire systems, but their function can remain a mystery, sometimes for decades.
A discussion of receptors can get complex rather quickly, so let’s just say that before 1992 all known receptors were simple switches. When bound with a ligand the receptor sends a signal. When not bound the receptor is silent.
The discovery of the first dependence receptor
In 1992 Dr. Bedesen’s lab at UCLA found a new receptor in an area of the brain that is greatly affected by Alzheimer’s. Using neural cells in a dish, Dr. Bredesen’s assistant Shahrooz Rabizadeh began producing cells with the gene p75NTR that in turn produced the receptor. Previous experiments had shown that neural cells with genes associated with Alzheimer’s would die almost en masse when exposed to stressors, which was in sharp contrast to cells that did not contain known Alzheimer’s genes. So naturally they assumed that upon exposure to its preferred ligand this receptor would produce a spectacular die-off of neurons. Instead, Rabizadeh found that the “stressor” had the opposite effect. The neurons whose new receptors was bound to the desired ligand were surviving. Importantly, the neurons whose receptors were unbound were dying rapidly.
The profound difference
All receptors studied before this were simple on off switches that only sent signals when bound. A dependence receptor however sends different signals depending on whether or not it is bound. In this sense it functions as a dead-man-switch. The significance of this is profound. If the dependence receptor binds to its preferred ligand, which in the case of the first dependence receptor was Netrin-1, it sends signals into the cell that conditions are good and growth is the order of the day. If the dependence receptor finds no ligand it sends signals into the cell that famine rules and the cell should self-destruct (apoptosis).
In real world terms this means that if a Netrin-1 dependence receptor in your brain fails to find Netrin-1 with which to bind it begins sending signals into the cell to commence apoptosis. The same is true for other dependence receptors looking for other ligand.
Think of the regular old receptor like the accelerator on a car. Apply pressure with your foot (ligand) and the signal is sent to move forward. Remove your foot from the accelerator and there is no signal. A dependence receptor is like a car that when your foot is removed from the accelerator immediately locks up the brakes or, worse, throws the transmission into park.
Note: as of 2019 there are about 2 dozen dependence receptors that have been identified. Much of the research has centered around the role of dependence receptors in cancer. This article is only concerned with Alzheimer’s and to that point “cell” means neuron.
The role of dependence receptors in Alzheimer’s
Needless to say, excessive apoptosis is bad. especially if your brain is killing off cells faster than they can be replaced. This, of course, is a hallmark of Alzheimer’s. Typically, brain atrophy in Alzheimer’s is initially concentrated in regions that control memory. As the disease progresses it moves to centers of control and function until the process reaches its climax of destruction.
The existence of dependence receptors and a lack of appropriate ligand help explain the more destructive aspects of Alzheimer’s. This all sounds bleak and yet it also implies that one can tip the balance from cell destruction to cell growth by keeping the brain supplied with appropriate ligand, thus halting or even reversing the process of Alzheimer’s. The result is an increase in brain cells and their corresponding functions. I would argue that this is the foundation upon which Dr. Bredesen has built a program for reversing Alzheimer’s. Providing adequate appropriate ligand is the goal of several aspects of his program. Hormone replacement therapy, supplementation (what he calls Trophic Support), exercise, diet, and even sleep are employed to keep dependence receptors happy and the brain healthy.
Many of you will want to know what supplements to take and in what quantities. I cannot make those recommendations, but I can point to an earlier article that detailed the formula for successfully reversing a mouse model of Alzheimer’s.
I am acutely aware that modern medicine by and large views supplementation as a quaint waste of time. Many an expert quips that taking vitamins produces “expensive urine.” This is fodder for several more articles, but I will summarize with this caveat that your brain is full of neurons and those neurons are bristling with dependence receptors. Starve those receptors at your own risk.