RSS Feed Print
Calcium overload and Alzheimer's disease
Lane Simonian
Posted: Saturday, January 30, 2021 1:57 PM
Joined: 12/12/2011
Posts: 5001



Nearly twenty years ago, when I first began studying Alzheimer's disease, I began by looking at all the major hypotheses for Alzheimer's disease and found out that almost none of them explained every case of the disease.  Only one of them--calcium dysregulation--was present in every case of Alzheimer's disease.  So when I read this article today it made me reflect back:

Does Calcium Overload Mark Dendritic Spines for Destruction?

The work supports the decades-old hypothesis that calcium dysregulation is a driver of neurodegeneration, noted Christopher Norris of the University of Kentucky in Lexington. “The present work … is yet another example of just how vital the ‘Ca2+ hypothesis’ is after all these years, and further cements the visionary status of its early proponents.”

https://www.alzforum.org/news/research-news/does-calcium-overload-mark-dendritic-spines-destruction

There are two sources of excess calcium in the brain.  One is the release of intracellular calcium.  Drugs like Aricept and Anavex 2-73 inhibit this release.  The second which is connected to the first is the influx of extracellular calcium which is usually the results of the over-activation of NMDA receptors which is inhibited by Namenda.  The first problem decreases with the progression of Alzheimer's disease whereas the second increases.  This may be why Aricept is only effective for awhile during the early stages of Alzheimer's disease whereas Namenda is only prescribed during the moderate to late stages of Alzheimer's disease.

My second step was trying to figure out what caused calcium dysregulation.  I found that there were many types of receptors (g protein-coupled receptors, receptor tyrosine kinases, ionotropic receptors) and many factors that contributed to this problem (high glucose levels, high fructose consumption, pesticides, air pollutants, viruses, bacteria, fungi, amyloid oligomers, misfolded tau proteins to name just a few).  Unless only receptor or only one factor caused someone's Alzheimer's disease, inhibiting any particular receptor or removing any particular factor was likely to make little difference in terms of the treatment of the disease.

The final step was to figure out what does excessive calcium trigger.  Calcium dysregulation leads to oxidants (hydrogen peroxide early on and then to peroxynitrite) and neuroinflammation which results in the production of more oxidants.  In addition to triggering neuroinflammation, peroxynitrite leads to a depletion of critical neurotransmitters needed for the retrieval of short-term memory, sleep, mood, social recognition, and alertness, inhibits neurotransmissions, inhibits the regeneration of neurons and synapses, causes DNA damage, damages tisssue, and results in the death of neurons.  The only way to largely stablize Alzheimer's disease is to scavenge peroxynitrite and to partially reverse the damage that it does to the brain.


Lurker123
Posted: Wednesday, February 3, 2021 12:30 PM
Joined: 1/25/2020
Posts: 6


"The only way to largely stablize Alzheimer's disease is to scavenge peroxynitrite and to partially reverse the damage that it does to the brain."

This conclusion is Lane's alone and is not supported by a strong body of scientific evidence. Lane's conclusions have been repeatedly refuted by anyone with scientific training who comes across them. For one example, see the comment section in this link:

https://theness.com/neurologicablog/index.php/alzheimers-and-stem-cells/

The link posted by Lane also never mentions peroxynitration. Below is a link to a review written by PhD-trained scientists on the mechanisms by which calcium dysregulation may be causing Alzheimer's disease. The authors suggest several strategies, but never once mention peroxynitration or that peroxynitrite scavengers can be used to treat disease.

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7763805/





Lane Simonian
Posted: Wednesday, February 3, 2021 1:35 PM
Joined: 12/12/2011
Posts: 5001


Alzheimer’s disease is a chronic and irreversible pathological process that has become the most prevalent neurodegenerative disease. Currently, it is considered a multifactorial disease where oxidative stress and chronic neuroinflammation play a crucial role in its onset and development. Its characteristic neuronal loss has been related to the formation of neurofibrillary tangles mainly composed by hyperphosphorylated tau protein. Hyperphosphorylation of tau protein is related to the over-activity of GSK-3β, a kinase that participates in several pathological mechanisms including neuroinflammation. Neuronal loss is also related to cytosolic Ca2+ homeostasis dysregulation that triggers apoptosis and free radicals production, contributing to oxidative damage and, finally, neuronal death. Under these premises, we have obtained a new family of 4,7-dihydro-2H-pyrazolo[3–b]pyridines as multitarget directed ligands showing potent antioxidant properties and able to scavenge both oxygen and nitrogen radical species, and also, with anti-inflammatory properties. Further characterization has demonstrated their capacity to inhibit GSK-3β and to block L-type voltage dependent calcium channels. Novel derivatives have also demonstrated an interesting neuroprotective profile on in vitro models of neurodegeneration. Finally, compound 4g revokes cellular death induced by tau hyperphosphorylation in hippocampal slices by blocking reactive oxygen species (ROS) production. In conclusion, the multitarget profile exhibited by these compounds is a novel therapeutic strategy of potential interest in the search of novel treatments for Alzheimer’s disease.

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7763805/


Lurker123
Posted: Thursday, February 4, 2021 8:31 AM
Joined: 1/25/2020
Posts: 6


Your quote:

"The only way to largely stablize Alzheimer's disease is to scavenge peroxynitrite and to partially reverse the damage that it does to the brain."

The authors state:

multitarget directed ligands showing potent antioxidant properties and able to scavenge both oxygen and nitrogen radical species, and also, with anti-inflammatory properties. Further characterization has demonstrated their capacity to inhibit GSK-3β and to block L-type voltage dependent calcium channels

So you are saying, "the only way to treat AD is to scavenge peroxynitrite"

The authors are saying "we need to target oxidative stress, nitrogen radical species, inflammation, and GSK-3B and calcium channels." And no, no matter what you post, the general scientific consensus does not think peroxynitrite causes all these other pathways to go wonky.

So by copy-pasting this you are proving my point. Thank you for agreeing!


Lane Simonian
Posted: Thursday, February 4, 2021 10:53 AM
Joined: 12/12/2011
Posts: 5001


There are certainly ways to treat Alzheimer's disease without scavenging peroxynitrite: inhibit intracellular calcium release, inhibit protein kinase C activity, inhibit NMDA receptors, inhibit P38 MAPK, inhibit inducible nitric oxide synthase, inhibit or prevent the overactivation of toll-like receptors.  But so far none of these approaches has done more than slightly slow down the progression of Alzheimer's disease.

You are already familiar with the links between peroxynitrite and many of the features of Alzheimer's disease.  Here are a couple of more.

https://pubmed.ncbi.nlm.nih.gov/11223641/

https://pubmed.ncbi.nlm.nih.gov/32739154/

It could be coincidence that the drugs/natural products (ginseng, Chinese herbs, Anavex 2-73) which are likely potent peroxynitrite scavengers appeared to largely stabilize cognitive function in people with Alzheimer's disease, but it is doubtful.