Here is the Second Draft: Part 1 of 3.
This was developed using Community Board input. Thanks. It is predominantly put together by 'laymen' as an exercise for learning more about what scientists are achieving with PBT2. It is not perfect, and there will likely be a third draft (more?) if we find enough new information or need to correct old info. Of course all credit goes to the patients, scientists and caregivers tackling AD one day at a time.
1. PBT2’s attraction force for Copper (Cu) and Zinc (Zn) is greater than ab amyloid’s (Abeta's) attraction force for these metals. (This prevents metallic misdirection by Abeta and prevents entanglement with Abeta.)
2. Because PBT2 prevents Cu/Zn attachment with Abeta, alpha and gamma secretase can resume naturally enzymatically-severing Abeta.
2a. Because secretase resumes severing Abeta, Abeta plaques no longer clog synaptic junctions.
2b. Because Abeta plaques no longer clog synaptic junctions; cell death is not caused by Abeta plaques clogging the synaptic junction.
3. Also, because PBT2 attracts Copper (Cu) and Zinc (Zn) better than Abeta; Copper and Zinc can attend to their normal roles in synaptic and neuron health; fortunately, PBT2 is a weaker metal attractant than other neuron components and releases these metals to resume their critical functions.
3a. In this way, PBT2 acts as a chaperone to shepherd Cu and Zn through the extra cellular matrix to their next functions without misdirection and entanglement with Abeta.
3b. Thus, for one example, after treatment with PBT2, Zinc is once again free to protect the integrity of microtubules inside the neuron by 'preventing' Hyperphosphorilation destruction of microtubules that would otherwise create toxic Tau entanglements which become prions.
3c. Because Zn can once again protect the integrity of microtubules inside the neuron, it can prevent yet another type AD cell neuron death that would otherwise occur if PBT2 was not administered.
Can you use this rewriting? two areas compiled
In Alz sufferers, LilrB2 resides on nerve cell surfaces and AB binds to LilrB2. This binding causes an enzyme Cofilin whose normal function is to break down Actin (a building-block protein essential to maintaining synaptic structure). This enzyme, now (through internal biochemical reorganization changes) increases its actin-busting, synapse-disassembling activity. No Actin,NoSynapse.
Neurons have a high constant demand for energy. Mitochondria generate the fuel required for cell function. Neurons are always on edge for maintaining adequate levels of energy production. A protein called PGC-1alpha helps regulate the operation and creation of Mitochondria. HTT mutant HD gene interferes with the level and functioning of PGC-1alpha. PGC-1alpha via a protein called TFEB serves a cleaner/renewal/recycler purpose. TFEB can prevent mutant HT genes from aggregation and neurotoxicity.
Seems to be some confusion regarding APP and Aβ. Alpha/Beta/Gamma secretase acts on APP. Beta and Gamma cutting APP creates Aβ40/42. Alpha cuts it in half (then gamma cuts same place as Aβ) and apparently it isn't long enough to "clump" with metals. As far as I understand secretase doesn't act on Aβ once created at any time. Once PBT2 acts on Aβ, the monomer Aβ is simply cleared if it is not needed (for immune response).
Might want to put something in about PBT2 once bound with Aβ metals the ligand +metals then easily passes neuron cell wall to deliver needed metals. Normal Signalling pathways then start up again and promote neuronal health and repair.
nyas dot org
Outstanding summary! A big thumbs-up for all three parts of your post. Your summary simultaneously illustrates the complexity of Alzheimer's and the possibility that a copper/zinc chaperone molecule such as PBT2 could address multiple disease mechanisms while producing minimal side effects. This makes me even more excited to see the Imagine Trial results.
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Part 2 of 3
4. Because the Abeta entanglements resume being cut at a natural rate, there is no feedback stimulation to overproduce alpha and gamma secretase. (In other words, no impenetrable plaque buildup means no overstimulation signal to overproduce alpha and gamma secretase)
5. Because alpha and gamma secretase is not overproduced, the vulnerable 'mutant' site on the APP molecules (as well as the 'normal' app molecules) is/are not cut more often than normal cell maintenance requires.
6. Because APP molecules are not enzymatically severed at an abnormally high rate, more APP molecules can function.
7. Because more APP molecules can function, neurons can be repaired and maintained thus preventing further cell death.
8. Also due to more APP molecules functioning, iron can once again be exported out of neuron cells thus preventing further neuron death from abnormal iron toxicity.
9. Because the APP resumes exporting iron from the neuron, this metal can also attend to its additional roles in neuron and synaptic health.
10. Because PBT2 does not inhibit normal BACE1 activity, Abeta formation can ebb and flow based upon normal neural activity that can, at times, temporarily require higher Abeta levels to fight such things as infection. (It has been determined that AD patients have a lower risk of cancer. This is possibly partly due to abnormally high levels of Abeta. Because PBT2 only returns Abeta levels back to a normal range, it will not increase the chance of cancer (due to lower Abeta) beyond that of the normal population).
11. Hippocampus neuron regeneration, with PBT2 therapy, results by returning equilibrium (normal functioning) to the brain (specifically normalizing interactions between APP, Abeta, Synaptic Junctions, Cu/Zn, and Fe as described previously.)
12. Because PBT2 treatment for AD produces new neuron growth in the hippocampus, executive function can be improved.
Part 3 of 3
13. BACE inhibitors do not work as well because BACE1 has other functions besides simply severing APP molecules. Moreover, some APP molecules needs to be severed to maintain cell integrity.
14. Strictly ab Amyloid scrubbers do not work because they only break up the plaques once formed, but this means stimulation to overproduce alpha and beta secretase continues. This means that APP molecules are severed at an abnormally high rate. This means little or no neuron repair and maintenance, and it means no ability for neurons to export iron. Thus copper, zinc and iron misdirection, inappropriate accumulation, or scarcity still occur.
15. Again, I think it is important to note that the Alzheimer's process kills cells in more than one way. 1. ab amyloid plaques combined with copper and zinc stick in synaptic junctions. 2. APP molecules are killed far more rapidly and cannot attend to their role in repairing and maintaining neurons, and they cannot export a lethal dose of iron from within the cell. 3. Copper, iron and zinc are misdirected and sequestered so they can't contribute to neuron health.