|
|
Joined: 4/24/2012
Posts: 484
|
http://www.alzheimersreadingroom.com/2014/11/tau-not-amyloid-beta-causes-neuronal.html
New research that dramatically alters the prevailing theory of how
Alzheimer’s disease develops has been published online today by
Georgetown researchers in the journal Molecular Neurodegeneration.
The research also helps explains why some people with plaque buildup in
their brains don’t develop dementia, and shows the potential of a cancer
drug to combat the disease.
“This study suggests a completely new way to look at Alzheimer's that
might alter the way we study the disease, screen for it and ultimately
treat it,” says the study’s senior investigator, Charbel E-H Moussa, MB,
PhD, of Georgetown University Medical Center.
NEURONAL DEATH
Moussa co-authored the study with researchers from Capital Medical
University in Beijing, China and Merck Research Laboratories, which
provided funding for the study.
The research team discovered that malfunctioning tau, not amyloid-beta
plaque, is the seminal event that spurs neuron death in disorders such
as Alzheimer’s disease.
Neuronal death occurs when tau, a protein found inside neurons, fails to function, the study shows.
GENES AND AGING
The role of tau is to provide a structure – somewhat like a train track
– inside brain neurons that allows the cells to clear accumulation of
unwanted and toxic proteins or “garbage.”
Malfunctioning tau can occur because of errant genes or through the
normal aging process. As some individuals grow older, tau can
malfunction, while enough normal tau remains to help clear the garbage.
“That explains the confusing clinical observations of older people who have plaque build-up, but no dementia,” Moussa explains.
COMMON CULPRIT
Moussa is an inventor on a Georgetown University patent application for
use of nilotinib, a drug approved to treat cancer, as a therapeutic
approach in neurodegenerative diseases.
The study shows that nilotinib can help the neuron clear the garbage if some functional tau remains.
“This drug can work if there is a higher percentage of good-to-bad tau
in the cell,” Moussa says, adding that many dementias have
malfunctioning tau and no plaque accumulation, such as a type linked to
Parkinson’s disease. “The common culprit is tau, so a drug that helps
tau do its job may help protect against progression of these diseases.”
|
|
Joined: 4/24/2012
Posts: 484
|
The cancer drug they mention is a tyrosine kinase inhibitor. I take that to mean that tyrosine phosphorylation of tau is involved in AD pathology? I think they are right about amyloid. However, amyloid has been shown to cause or lead to tau fibrilization (tangles). So amyloid may not be causing AD directly, but could it be part of the pathology? Why then have amyloid clearing drugs not worked?
|
|
Joined: 12/12/2011
Posts: 5161
|
Inhibiting tyrosine kinases may be important to the prevention and treatment of Alzheimer's disease and various cancers. Overactivation of tyrosine kinases lead to the formation of peroxynitrites. In cancer, peroxynitrites maintain the activation of the phosphatidylinositol 3-kinase/Akt pathway leading to cellular/tumor growth (by inhibiting an enzyme called PTEN). In the brain, peroxynitrites inhibit the neuroprotective phosphatidylinositol 3-kinase/Akt pathway via nitration. This contributes to tau hyperphosphorylation and nitration of tyrosine residues and cellular death.
http://www.fasebj.org/content/20/9/1431.long
http://www.ncbi.nlm.nih.gov/pubmed/16410804
The link between amyloid and tau may not be a direct one. The pathways that lead to amyloid oligomers and plaques are the same ones that lead to pre-fibril tau and neurofibrillary tangles. One pathway is controlled by peroxynitrites; the other by calpains. These two pathways often overlap and in that case you will have plaques, tangles, and Alzheimer's disease. But they do not always overlap, so it is possible to have amyloid and tangles without Alzheimer's disease (calpain activation with relatively low levels of peroxynitrites: children exposed to high levels of pollution in Mexico City, for instance) and to have Alzheimer's disease without much amyloid and tangles (high levels of peroxynitrites without much calpain activity--inhibition by caffeine or heparin, for instance).
http://www.genome.jp/kegg-bin/show_pathway?hsa05010
|
|
Joined: 4/24/2012
Posts: 484
|
Looking at peroxynitrite and insulin and nitration. Came up with this interesting link:
Reduction of insulin-stimulated glucose uptake by peroxynitrite is
concurrent with tyrosine nitration of insulin receptor substrate-1.
http://www.ncbi.nlm.nih.gov/pubmed/15240096
|
|
Joined: 12/12/2011
Posts: 5161
|
This is a very important study because it links peroxynitrite-mediated tyrosine nitration to insulin resistance and type 2 diabetes. When the glucose cannot get into the cells in the rest of the body, it goes to the brain where it increases myo-inositol levels and initially activates the platelet derived growth factor receptor (another receptor tyrosine kinase involved in Alzheimer's disease).
http://www.ncbi.nlm.nih.gov/pubmed/8603774
http://www.ncbi.nlm.nih.gov/pubmed/12645527
There is a big debate as to whether insulin resistance in the brain itself plays a role in Alzheimer's disease. At the very least, peroxynitrites and other oxidants disrupt glucose transport in the brain.
|
|
Joined: 12/12/2011
Posts: 5161
|
A short list of articles discussing how tyrosine nitration effects the brain in Alzheimer's disease.
Tyrosine nitration of a synaptic protein synaptophysin contributes to amyloid beta-peptide-induced cholinergic dysfunction.
Two distinct signaling pathways regulate peroxynitrite-induced apoptosis in PC12 cells.
Phosphatidylinositol 3-kinase is a target for protein tyrosine nitration.
Inhibition of acetylcholine synthesis and tyrosine nitration induced by peroxynitrite are differentially prevented by antioxidants.
On the other hand, NMDA receptors and the src kinase (a family of tyrosine kinases) are activated by peroxynitrites via nitration which also contributes to the death of neurons.
Interesting antioxidants convert peroxynitrites and hydrogen peroxide into water and water is a de-nitrating agent. So these antioxicants not only scavenge oxidants they partially reverse their damage.
http://www.ncbi.nlm.nih.gov/pubmed/10630617
Regarding amyloid, the c-terminal fragment (which increases peroxynitrite formation) is more toxic than amyloid oligomers (which increases hydrogen peroxide formation) is more toxic than amyloid plaques (which increases neither). And pre-fibral tau is more toxic than neurofibrillary tau tangles.
In rTg4510, a regional dissociation between neuronal loss and the accumulation of NFT [neurofibrillary tangles] is observed; there is a loss of neurons in the dentate gyrus before NFT lesions appear and, conversely, NFT appear without major cell loss in the striatum [68]. Likewise, many of the neurons that accumulate NFT in aged transgenic mice overexpressing normal htau seem "healthy" in terms of nuclear morphology, while a number of dying neurons do not appear to have a significant load of tau filaments [69]. Furthermore, using models based on quantitative data on neuron loss and NFT formation as a function of disease duration, it is estimated that CA1 hippocampal neurons in AD can survive with NFT for approximately 20 years [70]. Together, these studies suggest that tau-mediated neuronal death does not require the formation of NFT. Rather, non-filamentous tau, as well as abnormally modified tau intermediates, may be neurotoxic. Indeed, tau can undergo numerous post-translational modifications and some of these modifications, like phosphorylation and glycosylation, are believed to occur early in the development of tau pathology [71,72]. However, it is not yet known which tau intermediates are critical for the development of the different stages of neurodegeneration and by which mechanisms these intermediates cause cellular injury.
Peroxynitrite (ONOO-), which is capable of both protein nitration and oxidation [173], leads to tau oligomerization in vitro and in neuroblastoma cells [174,175]. Yet, it is believed that this effect results from the oxidative role of peroxynitrite and the formation of dityrosine bonds in tau[175]. The overall effect of tau nitration by peroxynitrite in vitro is to delay the polymerization of tau into filaments [175,176]. The toxicity of tau nitration may instead result from the inhibitory effect of nitration on the ability of tau to promote tubulin assembly which could compromise microtubule function [177].
http://www.molecularneurodegeneration.com/content/4/1/13
So well amyloid oligomers and neurofibrillary tangles may do some damage to the brain, they are not the principal cause. The principal cause is peroxynitrite. This explains why medications targeting amyloid oligomers and plaques and neurofibrillary tangles have failed to treat Alzheimer's disease in clinical trials while those targeting peroxynitrites have succeeded.
|
|
|
|