Technical stuff
Brain cells have on their surface a protein called APP, which is a dependence receptor. It is like a self-destruct switch whose default is in the ON position. The protein that binds to the receptor is a neurotrophin ligand, and in the absence of the neurotrophin ligand, the receptor signals the cell to die.
APP cleavage is the core process that led Bredesen down a path to his understanding of the etiology of AD 16 years ago. APP is Amyloid Precursor Protein, and it is sensitive to dozens of kinds of signals, adding up the pros and the cons to make a decision, to go down one of two paths. It can be cleaved in two, creating signal molecules that cause formation of new synapses and formation of new brain cells; or it can be cleaved in four, creating signal molecules that lead to trimming back of existing synapses, and eventually, to apoptosis, cell suicide of neurons.
In a healthy brain, these two processes are balanced so we can learn new things and we can forget what is unimportant. But in the Alzheimer's brain, destruction dominates creation, and the brain withers away.
On the right, one of the fragments is beta amyloid. Beta amyloid blocks the dependence receptor, so the receptor cannot receive the neurotrophin ligand that gives it permission to go on living. Beta amyloid is one of the 4 pieces, when the APP molecule goes down the branch where it is split in 4.
One of the signals that determines whether APP splits in 2 or in 4 is beta amyloid itself. This implies a positive feedback loop; beta amyloid leads to even more beta amyloid, and in the Alzhyeimer's patient, this is a runaway process. But positive feedback loops work in both directions--a boon to Bredesen's clinical approach. If the balance in signaling can be tipped from the right to the left pathway in the diagram above, this can lead to self-reinforcing progress in the healing direction. In the cases where Bredesen's approach has led to stunning reversals of cognitive loss, this is the underlying mechanism that explains the success.
Amyloid has been identified with AD for decades, and for most of that time the mainstream hypothesis was that beta-amyloid plaques cause the disease. (Adherents to this view have been referred to jokingly as BAPtists.) But success in dissolving the plaques has not led to restored cognitive function. In Bredesen's narrative, generation of large quantities of beta amyloid are a symptom of the body's attempts to triage a dying brain.
To tip the balance back toward growing new synapses
Having identified the focal point that leads to AD, Bredesen went to work first in the lab, then in the clinic, to identify processes that tend to tip the balance one way or the other. He has compiled quite a list. This is just a sampling:
- Increase autophagy
- Reduce homocysteine
- Increase insulin sensitivity
- Enhance mitochondnal function and biogenesis
- Reduce oxidative damage and optimize ROS (reactive oxygen species) production (but don't try to eliminate ROS!)
- Optimize estradiol
- Optimize progesterone
- Optimize TSH (thyroid-stimulating llormone) and thyroid function genarally
- Optimize pregnenolone
- Optimize testosterone
- Optimize cortisol
- Optimize DHEA (deliydroepiandrosterone)
- Reduce inflammation
- Enhance detoxification
- Increase glutathione
- Increased zinc, less copper
- Increased magnesium
- Increase vitamin D
- Reduce NF-kB, a signal that promotes inflammation
- Increase telomere length
Three primary types of AD
Bredesen's diagnosis begins with classifying each case of AD into one of three broad constellations of symptoms, with associated causes.
Type I is inflammatory. It is found more often in people with carry one or two ApoE4 alleles (a gene long associated with Alzheimer's) and runs in families. Laboratory testing will often demonstrate an increase in C- reactive protein, in interleukin-2, tumor necrosis factor, insulin resistance and a decrease in the albumin:globulin ratio.Type II is atrophic. It also occurs more often those who carry one or two copies of ApoÃŽ µ4, but occurs about a decade later. Here we do not see evidence of inflammatory markers (they may be decreased), but rather deficiencies of support for our brain synapses. These include decreased hormonal levels of thyroid, adrenal, testosterone, progesterone and/or estrogen, low levels of vitamin D and elevated homocysteine.
Type III is toxic. This occurs more often in those who carry the ApoÃŽ µ3 allele rather than ApoÃŽ µ4 so it does not tend to run in families. This type tends to affect more brain areas, which may show neuroinflammation and vascular leaks on a type of MRI called FLAIR, and associated with low zinc levels, high copper, low cortisol, high Reverse T3, elevated levels of mercury or mycotoxins or infections such as Lyme disease with its associated coinfections.
(Note: You can view every article as one long page if you sign up as an Advocate Member, or higher).
1
1
1
