RSS Feed Print
Charting Alzheimer's Disease(1)
Lane Simonian
Posted: Friday, January 24, 2020 6:11 PM
Joined: 12/12/2011
Posts: 4854


The following chart captures most of the pathways that lead to Alzheimer's disease


                                                                    Myo-inositol

    ↓

                Phosphatidylinositol 4,5 Bisphosphonate

 

G protein-coupled receptor or Receptor Tyrosine Kinase                                                                                                                                        

                    ↓                                                                             

Phospholipase C acting upon phosphatidylinositol 4,5 bisphosphonate

                     ↓

Inositol 1,4,5 triphosphate

                      ↓

Intracellular calcium release (along with phospholipase C activation of diacylglycerol)

                       ↓

Protein Kinase C           →      NMDA Receptor

                                                              ↓

                                                   Calcium Influx

                                                               ↓

                                                    Neuronal Nitric Oxide Synthase

                                                       ↓                         ↓

NADPH oxidase        p38  MAPK and NFkB

                                                      ↓                           ↓       

                                     Superoxide Anions      Inducible Nitric Oxide

                                                    ↘                                    ↙

                                                               Peroxynitrite

Here are some key quotes and information:

Myo-inositol

"Comparison of patients with progressive disease versus those who developed AD for the cingulate gyrus showed the increased myo-inositol-to-water ratio to be 72% predictive for dementia; similarly for the hippocampus, it was 70% predictive for dementia." 

Factors that increase myo-inositol in the brain are high glucose levels, high blood pressure due to high sodium levels, and Down syndrome (due to an extra chromosome containing the sodium/myo-inositol co-transporter).  Factors that lower myo-inositol levels are lithium (low dose lithium in water may lower risks for Alzheimer's disease, taxol (which may also reduce the risk for Alzheimer's disease) and estrogen (which may not help after awhile because it also activates a g protein-coupled receptor).

Receptor Tyrosine Kinases

Factors which overactivate these kinases include hyperinsulinemia, high fructose corn syrup, and certain chronic bacterial, viral, and fungal infections.

G Protein Coupled Receptors

Factors which overactivate these kinases include stress, various air pollutants, several pesticides and herbicides, some industrial solvents, misfolded tau proteins, and amyloid oligomers.  One of the g protein-coupled receptors antagonists being studied for Alzheimer's disease is Montelukast.

Protein Kinase C

"Malinow’s team found that when mice are missing the PKC alpha gene, neurons functioned normally, even when amyloid beta was present. Then, when they restored PKC alpha, amyloid beta once again impaired neuronal function. In other words, amyloid beta doesn’t inhibit brain function unless PKC alpha is active."

Prodrugs for the Protein Kinase C inhibitor riluzole are being studied for the treatment of Alzheimer's disease.

NMDA Receptors and the subsequent production of oxidants (hydrogen peroxide early in the disease and peroxynitrite increasingly as the disease progresses).

"We suggest that oxidative stress mediated through NMDAR and their interaction with other molecules might be a driving force for tau hyperphosphorylation and synapse dysfunction. Thus, understanding the oxidative stress mechanism and degenerating synapses is crucial for the development of therapeutic strategies designed to prevent AD pathogenesis."

Nuclear Factor kappa Beta inhibitors

Suppression of the nuclear factor-kappaB activation pathway by spice-derived phytochemicals: reasoning for seasoning.

"The activation of nuclear transcription factor kappaB has now been linked with a variety of inflammatory diseases, including cancer, atherosclerosis, myocardial infarction, diabetes, allergy, asthma, arthritis, Crohn's disease, multiple sclerosis, Alzheimer's disease, osteoporosis, psoriasis, septic shock, and AIDS. Extensive research in the last few years has shown that the pathway that activates this transcription factor can be interrupted by phytochemicals derived from spices such as turmeric (curcumin), red pepper (capsaicin), cloves (eugenol), ginger (gingerol), cumin, anise, and fennel (anethol), basil and rosemary (ursolic acid), garlic (diallyl sulfide, S-allylmercaptocysteine, ajoene), and pomegranate (ellagic acid). For the first time, therefore, research provides "reasoning for seasoning."

P38 MAPK inhibitors

Recent Advances in the Inhibition of p38 MAPK as a Potential Strategy for the Treatment of Alzheimer's Disease.

P38 mitogen-activated protein kinase (MAPK) is a crucial target for chronic inflammatory diseases. Alzheimer's disease (AD) is characterized by the presence of amyloid plaques and neurofibrillary tangles in the brain, as well as neurodegeneration, and there is no known cure. Recent studies on the underlying biology of AD in cellular and animal models have indicated that p38 MAPK is capable of orchestrating diverse events related to AD, such as tau phosphorylation, neurotoxicity, neuroinflammation and synaptic dysfunction. Thus, the inhibition of p38 MAPK is considered a promising strategy for the treatment of AD. In this review, we summarize recent advances in the targeting of p38 MAPK as a potential strategy for the treatment of AD and envision possibilities of p38 MAPK inhibitors as a fundamental therapeutics for AD.

Inducible Nitric Oxide Synthase Inhibitors

Brains from subjects who have Alzheimer's disease (AD) express inducible nitric oxide synthase (iNOS). We tested the hypothesis that iNOS contributes to AD pathogenesis. Immunoreactive iNOS was detected in brains of mice with AD-like disease resulting from transgenic expression of mutant human beta-amyloid precursor protein (hAPP) and presenilin-1 (hPS1). We bred hAPP-, hPS1-double transgenic mice to be iNOS(+/+) or iNOS(-/-), and compared them with a congenic WT strain. Deficiency of iNOS substantially protected the AD-like mice from premature mortality, cerebral plaque formation, increased beta-amyloid levels, protein tyrosine nitration, astrocytosis, and microgliosis. Thus, iNOS seems to be a major instigator of beta-amyloid deposition and disease progression. Inhibition of iNOS may be a therapeutic option in AD.

Peroxynitrite

The damage done by peroxynitrite in the brain includes damage to transport systems, enzymes, and receptors resulting in lower levels of neurotransmitters needed for the retrieval of short-term memory, sleep, mood, social recognition, and alertness, inhibition of the regeneration of neurons and synapses in the hippocampus, inhibition of glucose transport and blood flow in the brain which can lead to delusions, DNA damage, inflammation (which can lead to more peroxynitrite formation), and the death of neurons.  Polyphenol compounds in plants can lower the production of peroxynitrite, scavenge peroxynitrite, and partially reverse oxidation and nitration which causes the problems listed above.  Sugars in brown seaweed and glutathione produced by certain probiotics can do the same.

It is now just a matter of time to determine which compounds derived from natural products are most effective in reducing certain aspects of cognitive decline while stabilizing and improving others.


Lane Simonian
Posted: Friday, January 24, 2020 9:33 PM
Joined: 12/12/2011
Posts: 4854


A couple of recent stories that fit into this: 

NEWS RELEASE 24-JAN-2020

Can lithium halt progression of Alzheimer's disease?

McGill researchers' findings show that may be the case

MCGILL UNIVERSITY

In a new study, however, a team of researchers at McGill University led by Dr. Claudio Cuello of the Department of Pharmacology and Therapeutics, has shown that, when given in a formulation that facilitates passage to the brain, lithium in doses up to 400 times lower than what is currently being prescribed for mood disorders is capable of both halting signs of advanced Alzheimer's pathology such as amyloid plaques and of recovering lost cognitive abilities. The findings are published in the most recent edition of the Journal of Alzheimer's Disease.

https://www.eurekalert.org/pub_releases/2020-01/mu-clh012420.php

Living near major roads linked to risk of dementia, Parkinson's, Alzheimer's and MS

"For the first time, we have confirmed a link between air pollution and traffic proximity with a higher risk of dementia, Parkinson's, Alzheimer's and MS at the population level," says Weiran Yuchi, the study's lead author and a PhD candidate in the UBC school of population and public health. "The good news is that green spaces appear to have some protective effects in reducing the risk of developing one or more of these disorders. More research is needed, but our findings do suggest that urban planning efforts to increase accessibility to green spaces and to reduce motor vehicle traffic would be beneficial for neurological health."

https://www.sciencedaily.com/releases/2020/01/200123152616.htm

Low dose lithium probably works better as a possible preventative measure than as a treatment.  Green spaces help to filter out pollutants and help people relax.  

There is a whole world beyond amyloid and tau (although both play some limited role in Alzheimer's).