Monthly Archives: November 2016


Oleocanthal is Capable of Killing a Variety of Human Cancer Cells in the Laboratory

Oleocanthal is a natural phenolic compound found in extra-virgin olive oil.  Specifically it is a phenylethanoid.  Its chemical structure is related to oleuropein, also found in olive oil.


Figure 1:  Oleocanthal molecular structure

Olecanthal is the sole phenolic compound that is responsible for the distinct irritation and pungency in extra virgin olive oil.  When consuming fresh extra virgin olive oil, there can be a burning and stinging peppery sensation that occurs in the back of the throat which is due to the oleocanthal content.  Extra virgin olive oil that is classified as “robust” contains the highest amounts of olecanthal. 

The bitterness and pungency of oleocanthal in the throat often leads to coughing and throat clearing.  In fact, high quality extra virgin olive oils are classified as either “one-cough”, two-cough” or “three-cough” oils.   One-cough olive oil is considered good and is still extra virgin olive oil.  A two-cough olive oil is better, where the oleocanthal levels are higher than a one-cough oil.  The three-cough extra virgin olive oil is considered “exceptional” and has the highest levels of oleocanthal.  Three-cough extra virgin olive oil has a “peppery” and “burning” sensation in the back of the throat.  1

Oleocanthal’s Wide Range of Biological Effects

Researchers have discovered through various studies that oleocanthal possesses a wide range of biological effects. Previous studies have reported its activity as:  2

  • a potent antioxidant
  • a nonsteroidal anti-inflammatory agent that inhibits COX-1 and COX-2
  • a neuroprotectant that alters the structure and function of the neurotoxins β-amyloid and Tau
  • an inhibitor of proliferation, migration, and invasion of human breast and prostate cancer cells through c-Met inhibition
  • an inhibitor of AMPK in colon cancer cell
  • an inhibitor of macrophage inflammatory protein-1α in multiple myeloma

A number of studies have shown that olecanthal possess some remarkable anti-cancer and chemopreventive properties. 

Three studies from 2014, 2015 and 2016 demonstrate the antiproliferative activity of oleocanthal against breast and prostate cancer, colon cancer and malignant melanoma.

Oleocanthal has been reported to have strong anti-inflammatory properties. Oleocanthal has a remarkable and selective activity for human melanoma cells versus normal dermal fibroblasts with IC50s in the low micromolar range of concentrations. Such an effect was paralleled by a significant inhibition of ERK1/2 and AKT phosphorylation and downregulation of Bcl-2 expression.  3 

Oleocanthal demonstrated that the EVOO extracts tested showed an antiproliferative effect on colon cancer cells through the interaction with estrogen-dependent signals involved in tumor cell growth.  4

Oleocanthal inhibits the growth of several breast cancer cell lines at low micromolar concentration in a dose-dependent manner. Oleocanthal treatment caused a marked downregulation of phosphorylated mTOR in metastatic breast cancer cell line (MDA-MB-231).  5 

Oleocanthal Kills Cancer Cells In Vitro

A recent study from January 2015 has shown that oleocanthal is capable of killing a variety of human cancer cells in vitro (in the laboratory) while leaving healthy cells unharmed.  6  The researchers focused on breast, pancreatic, and prostate tumor cells.  They applied oleocanthal to these cancer cells and discovered that the cancer cells were dying very quickly – within 30 minutes to an hour. Normal programmed cell death, known as apoptosis, usually takes between 16 and 24 hours to complete its process. 

What they found was that oleocanthal pierces cancer cells’ lysosomes, the organelle in the cell cytoplasma that store the cell’s waste products, releasing enzymes that kill the cell. Oleocanthal caused a temporary halt in the life cycle of non-cancerous cells for a 72 hour period at which time they returned (awakened) to their normal proliferation, thus sparing the healthy cells from programmed cell death.

Image result for Lysosome

Figure 2:  Location of the Lysosome in the human cell

The lysosomes act as the waste disposal system of the cell by digesting unwanted materials in the cytoplasm, both from outside of the cell and obsolete components inside the cell.  Material from the outside of the cell is taken-up through endocytosis, while material from the inside of the cell is digested through autophagy.

lysosomeanatomyFigure 3:  Anatomy of the Lysosome

Lysosomal membranes of cancerous cells are weaker than those of non-cancerous cells, so inducing apoptotic cell death of permeable lysosome membranes may kill the cancerous cells.  This is exactly what the researchers discovered was happening when oleocanthal was applied to cancerous cells.  Oleocanthal mediated cancer cell death is promoted by destabilization of the lysosomal membrane, leading to the induction of lysosomal membrane permeabilization (LMP).

Effectively, the oleocanthal punctured the weak and destabilized lysosome cell membrane which then killed the cancerous cells via their own enzymes.  Healthy cells avoided being punctured by oleocanthal since their lysosome cell membrane was strong and stable.

The researchers concluded their study with the promising statement:  7

“Compounds that induce lysosomal membrane destabilization, such as OC, represent a viable method to exploit the vulnerability of the enlarged lysosomes in cancer cells. Our data suggest that the chemopreventive activity of EVOO is due to the ability of its bioactive phenolic components, especially OC, to induce cell death by entering the lysosome and inhibiting ASM activity, which induces LMP. Therefore, the ability of OC to induce LMP in cancer cells, but not normal cells, represents a novel therapeutic strategy for treating a large number of cancer types in which lysosomes are enlarged and more sensitive to lysosomotropic agents.”

Hunter College's David Foster on NBC


High Phenolic Extra Virgin Olive Oils

Apollo Olive Oil

The Governor

Rallis Olive Oil

Oleoestepa Hojiblanca

Ashwagandha (Withania somnifera) Root Extract Enhances Telomerase Activity

It is generally accepted that the shortening of telomeres, the DNA repeat sequences at the end of linear eukaryotic chromosomes, is a major factor that accelrates aging and causes various bodily systems to degenerate. 

Telomeres are the caps at the end of the DNA that conserve chromosome integrity and stability.  During the process of DNA replication, telomeres are shortened by 50 – 100 bp with each cell division. The end replication problem leads to critically short telomeres and ultimately senescence. As a result, telomeres are implicated as one of the factors that determine aging and lifespan.

Telomerase is a ribonucleoprotein enzyme that reverses transcriptase activity and carries out telomere replication by adding a species-dependent telomere repeat sequence to the 3′ end of telomeres. Telomerase synthesizes telomeric DNA sequences through the addition of TTAGGG repeats at the chromosome ends.

When telomerase is turned off in knockout mice, the result leads to degeneration of multiple systems, including immune, digestive and the nervous system.  When telomerase is turned back on, these degenerations are reversed.  Thus, telomerase activity is essential to health.

Enhancing telomerase activity is one way to delay aging.

One particular natural substance that has been shown to enhance the activity of telomerase is Ashwagandha (Withania somnifera), an Ayurvedic medicinal herb. 


Figure 1:   Ashwagandha (Withania somnifera) Root

A study published in 2016 from the Center for Preclinical and Translational Medicine Research, Central Research Facility, Sri Ramachandra University, Chennai, India, evaluated Ashwagandha root extract powder (KSM-66) suspended in water to enhance telomerase activity.  1

The researchers treated human cervical carcinoma cell lines called HeLa with various concentrations of Ashwagandha root extract, which showed an increase in telomerase activity measured with the established Telomerase Rapid Amplification Protocol (TRAP) assay.  Ashwagandha root extract powder, at a concentration of 10 µg – 50 µg/ml, increased telomerase activity by ~45%, in the Human HeLa cell line upon 72 hrs exposure.

The researchers concluded that Ashwagandha root extract has anti-aging inducing potential.

Informational Reference:

Ixoreal Biomed – KSM-66 Ashwagandha

Colostrinin Shows Promise as a Retardant to the Development of Dementia and Alzheimer’s Disease

Colostrinin is a naturally occurring mixture of at least 32 peptides (proline-rich polypeptides) derived from colostrum.  Colostrum is a form of milk produced in late pregnancy of mammals, including humans, by their mammary glands.  Colostrum delivers its nutrients in a very concentrated low-volume form to the delicate and immature digestive systems of a newborn.

Colostrinin may appear under various names in the literature, including:

  • CLN
  • Transfer factor
  • Proline-rich polypeptides (PRPs)

Numerous studies on Colostrinin have indicated that it has profound effects on cognitive performance and improvements in cognitive function.  Research demonstrates that an increase in new nerve cell growth and connectivity is observed after supplementing with Colostrinin.

Studies on cultured cells showed that Colostrinin modulates intracellular levels of reactive oxygen species (ROS), via regulation of glutathione metabolism, activity of antioxidant enzymes and mitochondria function. Due to an improvement in senescence-associated mitochondrial dysfunction and a decrease in ROS generation, Colostrinin decelerates the aging processes of both cultured cells and experimental animals. When given orally to mice, Colostrinin increased the lifespan and improved various motor and sensory activities.   1

Colostrinin’s Impact on Dementia and Alzheimer’s disease

There has been significant and considerable research on Colostrinin’s therapeutic value in dementia and Alzheimer’s disease.  Results from one study showed that oral administration of Colostrinin improves the outcome of Alzheimer’s disease patients with mild to moderate dementia.  2 

Specifically, the various neurological mechanisms of Colostrinin have been identified as the following:  3

  • changes the expression of molecular networks involved in beta amyloid protein production and in the changes to tau proteins that trigger formation of neurofibrillary tangles
  • alters the expression of genes to increase the production of enzymes that break down and eliminate beta amyloid as part of the natural clearance process
  • enhances defenses against chemical stresses and decreased expression of cytokines that promote inflammation

The studies on Colostrinin applied to dementia and Alzheimer’s disease have been encouraging and positive. 

A summary of these studies include:

In a study from 1996, 46 Alzheimer’s disease patients were randomly assigned to receive, every second day, either 100 mcg of colostrum, 100 mcg of selenium, or placebo tablets.  The patients took the supplements for three weeks, followed by 2 weeks of no treatment, and repeated this cycle 10 times over the one-year trial.

Subjects were then assessed using the standard Mini-Mental State Examination score. In the Colostrinin group, 54% of Alzheimer’s patients showed improved scores.  In the other 46% of Alzheimer’s patients receiving Colostrinin, the dementia progression stabilized and did not worsen.

In the placebo group, Alzheimer’s patients with mild and moderate disease saw their mental test scores decrease by 36% and 55%, respectively. 4

Another study from 2010 demonstrated that Colostrinin significantly relieved amyloid-beta induced cytotoxicity and alleviated the effect of amyloid-beta induced cytotoxicity.  5 

Colostrinin induces neurite outgrowth of pheochromocytoma cells and inhibits beta amyloid-induced apoptosis.  6  Colostrinin treatment may control the expression of genes that are involved in the development, maintenance, and regeneration of neurons in the central nervous system, and thus may also explain the improvements observed in Alzheimer’s patients with mild-to-moderate dementia during treatment with Colostrinin.

Low doses of Colostrinin (2.5 nM) can attain cytotoxic protection levels similar to those of highest doses (0.25 microM).  Thus, the time course for the appearance of beta-amyloid fibrils coincides with that for cytotoxicity, and that the reduction of fibrils of beta-amyloid peptides by Colostrinin is concomitant with the reduction of the cytotoxic effects of beta-amyloid on SHSY-5Y neuroblastoma cells.  These studies suggest that the neuroprotective effects exerted by Colostrinin are related to the reduction of beta-amyloid fibrils.   7

Colostrinin, which has efficacy in counteracting neural degradation and in stimulating neural growth, might prove to be a more effective means to deal with the causes of Alzheimer’s and other neurodegenerative diseases.  Evidence for the clinical efficacy of Colostrinin shows the remarkable ability of Colostrinin to reduce oxidative stress, prevent beta-amyloid aggregation and prolong the lifespan in a laboratory model of premature ageing.   8

Transcriptomal analysis showed that Colstrinin alters gene expression of molecular networks implicated in Abeta precursor protein synthesis, Tau phosphorylation and increased levels of enzymes that proteolitically eliminate Abeta.   9

A study from 2013 the beneficial effects of Colostrinin in the case of Alzheimer’s disease were shown in double-blind placebo-controlled trials, in long-term open-label studies and in multicenter clinical trials. A very important property of Colostrinin and one of its components, a nonapeptide (NP), is the prevention of amyloid-beta aggregation and the disruption of aggregates already formed. Moreover, Colostrinin has been found to modulate neurite outgrowth, suppress uncontrolled activation of cells, and reduce 4-HNE-mediated cellular damage.  10

These various studies demonstrate that Colostrinin is a very promising preparation which can be used to retard the development of dementia and Alzheimer’s disease.

Water and the Human Body Series: Chapter 4 – Water Output by the Human Body

When the body is in a balanced and healthy state, or what is known as homeostasis, the body is not designed to store water.  However, if the body is in a diseased state, the body has means to store water.  (See Chapters on Dehydration, Hyponatremia and Edema -Fluid retention)

Water is being lost by the body on a constant basis, so the water content of the body is constantly changing.

Water loss from the human body is classified as either sensible loss or insensible loss.  Sensible” loss is loss that can be perceived by the senses and can be measured.  Insensible losses can neither be perceived nor measured directly. You’ve lost it, but you don’t know that you’ve lost it.

Sensible loss:

  • Through the kidneys (urine excretion)
  • Through the gastro-intestinal tract (feces)

Insensible loss:

  • Trans-epidermal diffusion: water that passes through the skin and is lost by evaporation (perspiration and sweating)
  • Evaporative water loss from the respiratory tract  (by breathing)

The quantity of water loss varies with the lifestyle and environmental conditions of the individual, such as, gender, body size, weather, clothing worn, activity levels and a whole range of other factors.  However, on average, a typical adult loses about 2.1 to 2.7 liters (L) of water per day, broken down as follows:

  • lungs     400–500 mL  (18.5%)
  • skin       400–500 mL  (18.5%)
  • stool      80–100 mL   (3%)
  • urine      1–1.6 L        (60%)

 Image result for human water output

Figure 1:  Average Intake and Output of water per day

An individual who engages in physical exercise or is in a hot environment will loss additional water via sweat.  The amount of additional water loss via sweat may be up to several liters per day.

The environmental factors that effect water loss for each bodily organ and system, include:

Skin and lungs – If the air is dry and hot, water loss is increased

Urine – Urine water loss is dependent on the volume of the fluid consumed and total losses by other routes.  Urine water loss is also dependent on sodium chloride content in the diet as well as protein consumption.  The more sodium chloride and protein consumed, the more water loss is decreased due to the limited capacity of the kidneys to concentrate the urine. If water intake is restricted, the kidneys will conserve water by producing a more concentrated urine.

To maintain a healthy homeostatic state, the intake of water should be more than the loss via skin, lungs and feces and the any surplus is excreted by the kidneys. Typically urinary volume largely depends on intake of water, which should exceed the average output, taking into consideration external factors such as exercise, diet and environment.

Previously published Chapters in the Series

Chapter 1 – Water Content in the Human Body

Chapter 2 – The Function of Water in the Human Body

Chapter 3 – Methods of Gaining Water into the Human Body

Future Chapters in the Series:

Chapter 5 – Water Balance in the Human Body

Chapter 6 – Dehydration

Chapter 7 – Waters Effect on Neurological Health

Chapter 8 – Edema – Fluid Retention

Oleocanthal From Extra Virgin Olive Oil Can Reduce the Accumulation of Amyloid-Beta and May Prevent Alzheimer’s

Oleocanthal, also known as deacetoxydialdehydic ligstroside aglycone, is a type of natural phenolic compound found in extra-virgin olive oil and is responsible for its bitter and pungent taste.   It was mentioned in the literature in 1993 as a compound found in virgin olive oil.   1   Dr. Gary Beauchamp discovered olecanthal by accident when he discovered that he tasted something in olive oil that was similar to ibuprofen, the anti-inflammatory that he was studying.  Upon further research, Dr. Beauchamp discovered the nonsteroidal anti-inflammatory molecule called olecanthal. 

The polyphenols that are contained in extra virgin olive oil are responsible for the key sensory characteristics of bitterness, pungency, and astringency. Oleocanthal produces a strong peppery stinging and burning pungent sensation at the back of the throat.  2  Oleocanthal is aptly named since oleo means olive and canth means sting and al stands for aldehyde.  3


Figure 1:  Olecanthal 3-D molecule

Oleocanthal has been demonstrated to have potential neuroprotective properties and contribute to preventing cognitive decline due to neurodegenerative diseases.  Numerous clinical and preclinical studies have shown that the neuroprotective properties of oleocanthal are obtained by consuming high phenolic extra virgin olive oil. 

Summary of Oleocanthal’s Effect on Dementia and Alzheimer’s disease

The five studies from 2009 to 2015 demonstrate the remarkable protective effects of Oleocanthal against the progression of dementia and Alzheimer’s disease.  

  • Oleocanthal abrogates fibrillization of tau by locking tau into the naturally unfolded state
  • Oleocanthal improves antibody clearance of toxic Amyloid beta-derived diffusible ligands (ADDLs)
  • Olecanthal increases the immunoreactivity of soluble Abeta species
  • Oleocanthal inhibits tau fibrillization and aggregation
  • Oleocantahal alters and changes ADDLs to where it cannot bind to the synapse
  • Oleocanthal enhances the clearance of amyloid-beta from the brain by increasing two major amyloid-beta transport proteins at the blood-brain barrier
  • Oleocanthal significantly decreases amyloid load

The role that oleocanthal plays in the reduced incidence of Alzheimer’s disease has been examined in the following five studies:

Study 1  August 2009

The reserachers demonstrate that oleocanthal abrogates fibrillization of tau by locking tau into the naturally unfolded state. They demonstrate oleocanthal forms an adduct with the lysine via initial Schiff base formation. Structure and function studies demonstrate that the two aldehyde groups of oleocanthal are required for the inhibitory activity. These two aldehyde groups show certain specificity when titrated with free lysine and oleocanthal does not significantly affect the normal function of tau.  4   

Study 2 October 2009

This study showed that oleocanthal increased the immunoreactivity of soluble Abeta species, when assayed with both sequence- and conformation-specific Abeta antibodies, indicating changes in oligomer structure. Analysis of oligomers in the presence of oleocanthal showed an upward shift in MW and a ladder-like distribution of SDS-stable ADDL subspecies. Amyloid beta-derived diffusible ligands (ADDLs) comprise the neurotoxic subset of soluble Abeta(1-42) oligomers, now widely considered to be the molecular cause of memory malfunction and neurodegeneration in Alzheimer’s disease. 

The study from October 2009 is very important because it shows that oleocanthal changes the protein Amyloid beta-derived diffusible ligands (ADDLs).  Amyloid beta-derived diffusible ligands (ADDLs) comprise the neurotoxic subset of soluble Abeta(1-42) oligomers, now widely considered to be the molecular cause of memory malfunction and neurodegeneration in Alzheimer’s disease.  ADDLs adhere to synapses in the brain and close them off. Oleocantahal alters and changes ADDLs to where it cannot bind to the synapse.  The result is a a slow down of the advancement of Alzheimer’s disease.  Oleocanthal also augments antibody clearance of ADDLs, therefore protecting hippocampal neurons from ADDL toxicity.  5

Additionally, treatment with oleocanthal improved antibody clearance of ADDLs.  6    

Study 3  July 2011

This study investigated the mechanism by which oleocanthal inhibits tau fibrillization and aggregation in vitro via covalent chemical interaction with the fibrillogenic fragment of tau proteins.  7 

Study 4 June 2013

The authors of this study applied different concentrations of oleocanthal over three days to mouse brain cell cultures. They also administered oleocanthal to live mice every day for two weeks. In both trials, levels of two proteins that play major roles in transporting beta-amyloid out of the brain as well as enzymes that degrade beta-amyloid increased significantly after administering oleocanthal.  oleocanthal enhances the clearance of amyloid-beta from the brain by increasing two major amyloid-beta transport proteins at the blood-brain barrier.  8   The results from the researchers demonstrated significant increase in 125I-Aβ40 degradation as a result of the up-regulation of amyloid-beta degrading enzymes following oleocanthal treatment. In conclusion, these findings provide experimental support that potential reduced risk of Alzheimer’s disease associated with extra-virgin olive oil could be mediated by enhancement of amyloid-beta clearance from the brain.

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Figure 2:  Oleocanthal 

(Source:  Olive-Oil-Derived Oleocanthal Enhances β-Amyloid Clearance as a Potential Neuroprotective Mechanism against Alzheimer’s Disease: In Vitro and in Vivo Studies)

Study 5  November 2015

In this study, the researchers investigated the effect of oleocanthal on pathological hallmarks of Alzheimer’s disease in TgSwDI, an animal model of Alzheimer’s disease. Mice treatment for 4 weeks with oleocanthal significantly decreased amyloid load in the hippocampal parenchyma and microvessels. This reduction was associated with enhanced cerebral clearance of amyloid-beta across the blood-brain barrier (BBB). Further mechanistic studies demonstrated oleocanthal to increase the expression of important amyloid clearance proteins at the BBB including P-glycoprotein and LRP1, and to activate the ApoE-dependent amyloid clearance pathway in the mice brains. Their conclusion was that findings from in vivo and in vitro studies provide further support for the protective effect of oleocanthal against the progression of Alzheimer’s disease.    9

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Figure 3:  Oleocanthal Enhances Amyloid-Beta Clearance

(Source:  Oleocanthal Enhances Amyloid-β Clearance from the Brains of TgSwDI Mice and in Vitro across a Human Blood-Brain Barrier Model)

Extra Virgin Olive Oil

Extra Virgin Olive Oil contains many polyphenols (at least 30) other than olecanthal, including:

  • 10-hydroxyligstroside
  • 10-hydroxyoleuropein
  • elenolic acid
  • flavonoids
  • hydroxytyrosol
  • lignans
  • ligstroside
  • oleuropein
  • pinoresinol
  • tyrosol

The grade of olive oil will determine the amount of polyphenols contained in the oil.  Ordinary grades of olive oil contain 50 ppm or less of polyphenols, depending on their percentage of refined olive oil. With Extra Virgin Olive Oil, the polyphenol content typically ranges between 100 to 250 ppm. Exceptional grades of Extra Virgin Olive Oil may be as high as 500 ppm.  This higher content of polyphenols will depend on a number of factors such as:

  • age of the oil
  • degree of ripeness
  • olive cultivar
  • production and extraction technologies employed

Extra virgin olive oil generally falls into three categories:

  • delicate
  • medium
  • robust

The robust olive oils tend to have the highest levels of polyphenols. This can be indicated by the olive oil having a strong peppery finish, a distinct bitterness and very intense flavors on the front end of the palate.

One company in Northern California that produces exceptional extra virgin olive oil is Apollo Olive Oil.  They utilize a state-of-the-art method of olive oil extraction that uses milling under vacuum, which dramatically improves the extraction of polyphenols and provides much more quality control over the entire milling process. This vacuum technology greatly reduces oxidation of the olive oil and thus produces excellent Extra Virgin olive oil with roughly triple the amounts of polyphenols, compared to conventional milling technologies. Only five such vacuum mills exist in the world, and Apollo Olive Oil was privileged to obtain one in 2005. 

The graph below demonstrates the higher polyphenols (in ppm) content of Apollo Olive Oils, known as Exceptional EVOOs.

Source:  Apollo Olive Oil

The Table below lists the varieties of EVOO produced by Apollo Olive Oil and the their polyphenol, tocopherol and total antioxidant content:

Polyphenols, Tocopherol and Total Antioxidant Content of Apollo Olive Oil Varieties

Name of Olive OilPolyphenolsTocopherols (Vitamin E)Total antioxidants
Mistral Organic398 mg/Kg258 mg/Kg656 mg/Kg
Sierra Organic430 mg/Kg256 mg/Kg686 mg/Kg
Grossane Organic472 mg/Kg278 mg/Kg750 mg/Kg
Aglandau Organic500 mg/Kg258 mg/Kg758 mg/Kg
Barouni683 mg/Kg230 mg/Kg913 mg/Kg
Coratina Organic650 mg/Kg301 mg/Kg951 mg/Kg
Source: Apollo Olive Oil

Apollo Olive Oil is the leader in polyphenol extraction from extra virgin olive oil.  It truly may be the healthiest olive oil you can find in the United States.

The Making of Apollo Olive Oil

Alzheimer's disease: how extra-virgin olive oil can prevent it - Amal Kaddoumi, Professor of Biopharmaceutics at University of Louisiana at Monroe


Apollo Olive Oil

Inhibiting the GSK-3 Enzyme with Lithium Orotate May Slow Brain Aging and Dementia

Prevention Strategy to Slow Brain Aging and Dementia

One important prevention strategy to combat the issue of brain aging and dementia, especially the development of Alzheimer’s disease, is to inhibit and reverse the structural changes and damages that occur in brains cells as part of normal aging.

Researchers have identified a number of these structural changes and defects.  The major structural defects include:

  • Beta amyloid accumulation: These neurotoxic plaques are protein clumps that damage the neuron and impede memory consolidation
  • Neurofibrillary tangles: Neurons are clogged with neurofibrillary tangles which develop when tau proteins are dysfunctional
  • Tau protein dysfunction: Neurons eventually die when tau proteins become dysfunctional and accumulate.  Tau proteins provide structure to the microtubules of the neuron which creates a cellular skeleton for the neuron

Glycogen Synthase Kinase-3 Enzyme (GSK-3)

Glycogen Synthase Kinase-3 Enzyme (GSK-3) is an enzyme in the body that, when normally activated, is part of the system regulating glucose metabolism. 

However, when GSK-3 is overly and excessively activated, it tends to damage cellular structures.  Excessively activated GSK-3 can result in the following health issues in the body:  1  2  3

  • Accelerates aging in heart and muscle
  • Accelerates aging in the skeletal system
  • Accelerates aging in the stomach and liver
  • Develops type II diabetes
  • Develops Alzheimer’s disease  4
  • Impairs autophagy which clears toxic debris inside cells
  • Increases pro-inflammatory cytokines

Glycogen Synthase Kinase-3 Enzyme (GSK-3) Contributes to Alzheimer’s disease

The structural changes and defects that occur in the aging brain which develops into dementia and eventually Alzheimer’s disease include accumulation of beta amyloid plaque and damaged tau proteins.  Both of these results in neurofibrillary tangles which lead to neuron death.

Increased or aberrant over-expressive activity of the GSK-3 enzyme is a contributing factor in these structural changes. 

Excessive GSK-3 damages (through the process of the hyperphosphorylation of tau proteins) tau proteins and is thought to directly promote amyloid beta production which leads to neurofibrillary tangles.  5

As mentioned, GSK-3 normally regulates glucose/insulin metabolism.  However, excessive GSK-3 may increase the development of Type II diabetes with glucose impairment and insulin resistance.  It is clear that Type II diabetes increases accumulations of beta amyloid and damaged tau proteins.  6

Because of this correlation, Alzheimer’s disease is often called Type III diabetes.

This conclusion lead to the Alzheimer’s strategy of inhibiting GSK-3 as a means to effectively lower blood glucose, while increasing insulin sensitivity.  7 

GSK-3 Inhibitors

Targeted inhibition of GSK-3 may have therapeutic effects with regards to mild cognitive impairment and dementia (including Alzheimer’s disease).  The identified GSK-3 inhibitors are of diverse chemotypes and mechanisms of action, which include inhibitors isolated from natural sources, cations (minerals), and synthetic small molecules.

The cation lithium was the first “natural” GSK-3 inhibitor discovered in 1996.  8


Lithium is a chemical element belonging to the alkali metal group.  It is highly reactive and flammable.  As a dietary mineral it is classified as a trace element and the available experimental evidence now appears to be sufficient to accept lithium as essential micronutrient.  The suggested provisional Recommended Daily Allowance (RDA) for a 70 kg (154 lbs.) adult is 1,000 micrograms (mcg) per day.

lithium-orotate-2d-skeletalFigure 1:  Lithium Orotate

Source: Public Domain:

The lithium content in food varies by the region where the food is grown and varied growing techniques.  Plant foods are richer in lithium than animal foods.  The foods that have the largest concentration of lithium are the nightshade plants, including:

  • eggplants
  • peppers
  • potatoes
  • tomatoes

Other foods that contain lithium in trace amounts include:

  • apples
  • bananas
  • cabbage
  • carrots
  • cauliflower
  • cinnamon
  • cucumbers
  • eggs
  • lemons
  • lentils
  • milk
  • mushrooms
  • seafood
  • seaweed
  • seeds
  • sugar cane

Tap water (at least in the United States) is virtually devoid of any lithium, unless it is intentionally treated with lithium.  Spring water, on the other hand, may contain trace amounts of lithium.

Because it may difficult to obtain the RDA of lithium daily from diet and water, the alternative is to supplement with a micro-dose lithium supplement (See Resources).

A study published in 2013 demonstrated that a microdose lithium amount of 300 mcg per day for 15 months stabilized cognitive impairment in patients with Alzheimer’s disease.  9  The patients of the study showed no further cognitive decline during the study period while they supplemented with the microdose lithium.

The researchers concluded that the microdose lithium inhibited the phosphorylation of GSK-3.  10

Lithium as GSK-3 Inhibitor

Lithium, which is a medication (as Lithium Carbonate) used for bipolar disorder, is a direct and indirect inhibitor of GSK-3.

The mechanism by which lithium inhibits GSK-3 is that lithium:  12

  • Is a competitive inhibitor of GSK-3 with respect to magnesium
  • Indirectly inhibits GSK-3 via enhanced serine phosphorylation and autoregulation
  • Inhibits potassium deprivation

In vitro, lithium has been shown to suppress tau phosphorylation, enhance tau–microtubule binding, and promote microtubule assembly.  In vivo, lithium has been shown to reduce insoluble tau and ameliorate axonal transport deficiencies in transgenic Drosophila.  13 

Further studies have shown that lithium chloride significantly decreases amyloid-beta production in vivo through inhibition of GSK-3 activity.  14 

The form of lithium used in these studies is lithium chloride, which is only available by prescription.  However, microdoses of a form of lithium that is not used in psychiatry has been shown to inhibit GSK-3.  15 

A study from 2015 examined a mouse model of Alzheimer’s disease where the researchers supplied mice with microdoses of lithium carbonate in their drinking water.  The mice that were treated with lithium retained the memory and cognitive performance of normal mice.  16  They also showed that the mice showed a decrease in amyloid-beta plaques in their brains.

Additional studies on lithium treatment for dementia demonstrates that lithium can:

  • block amyloid precursor protein (APP) deposits  17
  • reduce amyloid-beta secretion in cells and transgenic mice overexpressing APP  18
  • reduce tauopathy in transgenic mice overexpressing human mutant tau   19

Water and the Human Body Series: Chapter 3 – Methods of Gaining Water into the Human Body

“Water does not stay in one place, it flows quickly and carves its own way, even through stone – and when something blocks its way, water makes a new path.”

— Memoirs of a Geisha

Three Methods of Gaining Water in the Body

There are 3 methods of gaining water in the human body:

  • Drinking water and other fluids (accounts for ~60%-70% of the total fluid gain)
  • Dietary intake of food  (accounts for ~30%-20% of the total fluid gain)
  • Metabolic water produced by human cells through cellular respiration  (accounts for ~10% of the total fluid gain)

Drinking water and other fluids

The most common way of adding water to the body is by drinking water or other fluids.  These other fluids will varying on the amount of water content, for example, pure water compared to vegetable juices. 

Some fluids may actually create a net fluid loss or at least not contribute to water gain in the body.  For example, ethanol or drinking water is approximately 60% water depending on the type of spirit, yet it can be a very dehydrating beverage in excess quantities and does not replenish water content in the human body.  

All water-containing drinks can contribute to the total required for hydration including fruit juice, soft drinks, tea, coffee, dilute alcoholic drinks such as beer, as well as pure water itself.

Dietary intake of food

Most foods, even those that look hard and dry, contain water. The body can get approximately 20 to 30 percent of its total water requirements from solid foods alone.

Living or raw foods have a higher content of water since they have not been cooked by heating.  Cooked foods usually have less water content, for example, cooked broccoli versus raw broccoli.  Processed foods may contain a very low water content and are not preferred in the diet for water gains.

The variety of the diet will dictate the amount of water consumed in the diet.  The higher the consumption of water-rich foods (e.g., fruits, vegetables or soup), the higher the intake of water from food. Fruits and vegetables are indeed the food group which contains the most water: from 96% in a cucumber to 72% in an avocado, most contain more than 85% water.

The Figures 1 and 2 below list the water content of various food:



Metabolic water

Metabolic water refers to water created inside a living organism through metabolism, by oxidizing energy-containing substances in their food. Humans obtain only about 8-10% of their water needs through metabolic water production.  

Each macronutrient that is metabolized in the body produces different quantities of water as a by-product.  Lipid (fat) oxidation produces the most water per gram.

The Table below illustrates the metabolic water production for all three macronutrients:   1

Metabolic Water from Macronutrients

Macronutrient in 100 gramsMetabolic Water Produced
Fat110 grams
Protein41.3 grams
Carbohydrate55 grams

One liter equals 1,000 grams, so 100 grams is the equivalent to 0.10 liters.

The amount of metabolic water produced by an average body is approximately 250 ml to 350 ml per day, depending on the variety of the diet.  Metabolic water production is proportional to the energy intake. As a result a sednetary individual may produce 250 ml of metabolic water per day versus a physically active individual engaging in strenuous exercise may produce up to 600 ml per day of metabolic water.

Metabolism of Water in the Body

Once water is ingested, it is absorbed in the gastrointestinal tract starting with the stomach in which a small portion is absorbed.  After leaving the stomach, water is absorbed mostly in the early segments of the small intestine, the duodenum and the jejunum. The small intestine absorbs about 6.5 liters per day and the colon absorbs about 1.3 liters per day.

From there the water enters the cardiovascular system by passing from the intestinal lumen into plasma mainly by passive transport, regulated by osmotic gradients.  The absorption process is very rapid where within 5 minutes after ingestion of water it us present in the plasma and blood cells. 

The vascular system then transports it to the interstitial tissue spaces between cells.  It then crosses the cell membrane via aquaporins, which are specific integral membrane proteins for water transport into the cell.

Image result for aquaporins

Figure 3:  Aquaporin illustration

Recommendations for daily water intake

Insufficient scientific research exists that addresses the issue of the amount of water required to prevent disease or improve health. Due to this no exact consumption thresholds clearly exist or are linked to a specific health benefit or risk.  However, there are a number of agreed upon guidelines as to the minimum amount of water to be consumed depending on a variety of factors, including age, weight, health status, gender, level of activity (exercise) and environment.

In 2010 the European Food Safety Authority (EFSA) published official guidelines for total water intakes.  These guidelines are based on physiological parameters based on age.  These recommendations assumes no physical activity which will account for extra fluid loss and will need to be restored.

The Table below lists the recommended adequate intake values for water:

Dietary Reference Values for Water

Age rangeDaily adequate water intake
0-6 months680  mL/day or 100-190  mL/kg/day. From human milk
6-12 months0.8-1.0  L/day. From human milk and complementary foods and beverages
1-2 years1.1-1.2  L/day
2-3 years1.3  L/day
4-8 years1.6  L/day
9-13 years – Males2.1  L/day
9-13 years – Females1.9  L/day
14-18 years – Males2.5  L/day
14-18 years – Females2.0  L/day
19-70 years – Males2.5  L/day
19-70 years – Females2.0  L/day
Special cases
Pregnant women2.3  L/day
Lactating women2.7  L/day

Source:  EFSA Panel on Dietetic Products, Nutrition, and Allergies (NDA); Scientific Opinion on Dietary reference values for water. EFSA Journal 2010; 8(3):1459. [48 pp.]. doi:10.2903/j.efsa.2010.1459.

Previously published Chapters in the Series

Chapter 1 – Water Content in the Human Body

Chapter 2 – The Function of Water in the Human Body

Future Chapters in the Series:

Chapter 4 – Water Loss by the Human Body

Chapter 5 – Water Balance in the Human Body

Chapter 6 – Dehydration

Chapter 7 – Waters Effect on Neurological Health

Chapter 8 – Edema – Fluid Retention

Previously published Chapters in the Series

Chapter 1 – Water Content in the Human Body

Chapter 2 – The Function of Water in the Human Body

Future Chapters in the Series:

Chapter 4 – Water Loss by the Human Body

Chapter 5 – Water Balance in the Human Body

Chapter 6 – Dehydration

Chapter 7 – Waters Effect on Neurological Health

Chapter 8 – Edema – Fluid Retention

Cholinergic Hypothesis of Alzheimer’s Disease and Potential Natural Therapies

The cholinergic hypothesis proposes that Alzheimer’s disease is caused by insufficient or reduced synthesis of the neurotransmitter acetylcholine. This acetylcholine deficiency hypothesis is not not widely supported because it does not address directly the underlying cause of the disease or the disease progression.

The clinical trials have shown that therapies that support acetylcholine may reduce the symptoms of Alzheimer’s disease, but do not reverse or stop the disease.  Inadequate acetylcholine synthesis is a consequence of generalized brain deterioration observed in Alzheimer’s disease as well as non-Alzheimer’s patients. 

Nevertheless, therapies that support acetylcholine are important to perhaps prevent Alzheimer’s disease and to maintain proper neurotransmitter balance.

Acetylcholine is the most abundant neurotransmitter in the brain. Acetylcholine is also produced in the Intestines.

According the National Health and Nutrition Examination Survey (NHANES) in 2003-2004, only about 10% of the population have an adequate intake of choline. This means about 90% of the population consumes a diet deficient in choline. Furthermore, those without an adequate intake of choline may not have symptoms.

Acetylcholine Deficiency Symptoms

Acetylcholine Deficiency 
Overall SymptomsPhysical Symptoms
Loss of MemoryArthritis
Cholesterol elevation
Difficulty urinating
Dry cough
Dry mouth
Eye disorders
Inflammatory disorders
Multiple sclerosis
Myasthenia gravis
Sexual dysfunction
Speech problems

Along with folate and B12 deficiency, inadequate consumption of choline can lead to high homocysteine levels and all the risks associated with hyperhomocysteinaemia, such as cardiovascular disease, neuropsychiatric illness (Alzheimer’s disease, schizophrenia) and osteoporosis. Inadequate choline intake can also lead to fatty liver or non-alcoholic fatty liver disease (NAFLD).

If the body’s choline levels are depleted or low, then the body will take the choline from the myelin sheaths to build more acetylcholine. 1  This is why it is paramount to provide the brain with enough choline so as not to compromise the integrity of the neurons.

Choline content of food

Adequate Intake (AI) levels for choline:

Population Adequate Intake (AI)
of Choline
Infants:(0-6 months)
(7-12 months)
125 milligrams
150 milligrams
Children:(1-3 years)
(4-8 years)
(9-13 years)
200 milligrams
250 milligrams
375 milligrams
Adolescents:(14-18 years) 400 milligrams (Females)
550 milligrams (Males)
Adults:(19 and older) 425 milligrams (Females)
550 milligrams (Males)
Pregnant women 450 milligrams
Breastfeeding women 550 milligrams


Brain speed is associated with acetylcholine. Reduction in brain speed is due to a loss of acetylcholine.

Brain speed should peak at a value of 300 milliseconds.  The difference between a vibrant brain speed (300 milliseconds) and dementia (390-400 milliseconds) is only 100 milliseconds.

Brain Processing Speeds

Brain Processing Speeds  
Chronological AgeBrain Speed (in MSec)Cognitive State
Age 30320Vibrant
Age 30330Normal
Age 30350Slight change in memory
Age 50 and beyond380Noticeable change in memory
Age 50 and beyond390-400Significant dementia
Source: Younger Brain, Smarter Mind, by Eric R. Braverman, M.D

A natural approach to enhancing acetylcholine is to focus on four areas of acetylcholine metabolism:

  • Enhance acetylcholine (upregulate acetylcholine production)
  • Enhance Cholinergic Receptors
  • Enhance Choline Acetylase
  • Inhibit Acetylcholinesterase

There are a number of recognized substances that enhance and produce acetylcholine.

Enhancing Acetylcholine

Ecklonia Cava1
Huperzine A2
Amino Acids
Acetyl-L-Carnitine (ALCAR)3
Bacopa Monneri7
Ginko Biloba8
Korean Ginseng9
MagnoliaHonokiol 10
St. John’s Wort11
Sunifiram (DM-235 )22
Vitamin B125
Vitamin B526
Vitamin B1227
Vitamin C28

Cholinergic receptors are a type of neurotransmitter receptor located on the postsynaptic cleft of neurons. Cholinergic receptors are responsible for receiving acetylcholine from the presynaptic clefts of other neurons.  Cholinergic receptors are integral membrane proteins that responds to the binding of acetylcholine.

Enhancing Cholinergic Receptors

Cholinergic Receptors  
Amino Acids
Acetyl-L-Carnitine (ALCAR)3
American Ginseng4
Korean Ginseng5
Ginko Biloba6
Alpha GPC9

Choline acetyltransferase is essential for the generation of Acetylcholine.  Choline acetyltransferase (commonly abbreviated as ChAT) is a transferase enzyme responsible for the synthesis of the acetylcholine.   ChAT catalyzes the transfer of an acetly group from the coenzyme acetyl-CoA, to choline yielding acetylcholine (ACh).

Enhancing Choline Acetyltransferase

Choline Acetyltransferase  
Amino Acids
Acetyl-L-Carnitine (ALCAR)1
MagnoliaHonokiol 2
Ginsenoside GM-14
Vitamin E7

Acetylcholinesterase is the most common type of Cholinesterase Esterase Hydrolase Enzyme present in the synaptic cleft of neurons – Acetylcholinesterase is manufactured by the Liver. Acetylcholinesterase breaks (hydrolyzes) acetylcholine down into its constituents – choline.  Inhibition of AChE leads to accumulation of ACh in the synaptic cleft.

Inhibit Acetylcholinesterase

Ecklonia Cava1
Huperzine A3
Ginko Biloba5
Green Tea6
MagnoliaHonokiol 7
Marjoram (Ursolic Acid) (also found in rosemary, lavender, oregano, thyme)15
Linalool (thyme and cinnamon)16
Sulfuric Compounds
Vitamin B619
Vitamin C20

Following is a summary of the substances that enhance acetylcholine.

Summary: Enhancing Acetylcholine

Summary: Enhancement of Acetylecholine      
Ecklonia CavaXX2
Huperzine AXX2
Amino Acids
Acetyl-L-Carnitine (ALCAR)XXX3
Ginko BilobaXXX3
Magnolia (Honokiol)XXX3
American GinsengX1
Korean GinsengXX2
Bacopa MonneriX1
St. John’s WortX1
Green TeaX1
Ginsenoside GM-1X1
Sunifiram (DM-235 )X1
Marjoram (Ursolic Acid) (also found in rosemary, lavender, oregano, thyme)X1
Linalool (thyme and cinnamon)X1
Sulfuric Compounds
Alpha GPCXX2
Vitamin CXX2
Vitamin B1X1
Vitamin B5X1
Vitamin B6X1
Vitamin B12X1
Vitamin EX1
AChR: Cholinergic Receptors
ChAT: Choline Acetylase
AChe: Acetylcholinesterase


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Natural Compounds as Potential Therapeutic Agents for Inhibiting and Decreasing Tau Protein in Alzheimer’s Disease

The development of Alzheimer’s disease is commonly explained by one of the three hypotheses or all three.  These hypotheses include:  1

  • Cholinergic hypothesis
  • Amyloid beta hypothesis
  • Tau hypothesis

The neurons of the brain consists of a cytoskeleton which acts as an internal support structure.  The cytoskeleton is partly made up of microtubules which are transportation channels that guide nutrients and molecules from the neuron body to the ends of the axon and back again to the neuron body. 

A stablizing protein imbedded into the microtubules is a protein called tau.  Tau is stablized in the microtubule by a process known as phosphorylation.  In the development of Alzheimer’s disease, tau undergoes chemical changes and becomes hyperphosphorylated.  The hyperphosphorylated tau begins to combine with other threads of hyperphosphorylated tau creating neurofibrillary tangles which ultimately disintegrates and collapses the neuron’s transportation system.  2

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Tau in healthy neurons and in tauopathies

Tau facilitates microtubule (MT) stabilization within cells and it is particularly enriched in neurons. MTs serve as “tracks” that are essential for normal trafficking of cellular cargo along the lengthy axonal projections of neurons, and it is thought that tau function is compromised in Alzheimer’s disease and other tauopathies. This probably results both from tau hyperphosphorylation, which reduces the binding of tau to MTs, and through the sequestration of hyperphosphorylated tau into neurofibrillary tangles (NFTs) so that there is less tau to bind MTs. The loss of tau function leads to MT instability and reduced axonal transport, which could contribute to neuropathology.

Source:  Advances in Tau-focused drug discovery for Alzheimer’s disease and related tauopathies

The Tau hypothesis states that the observation of amyloid beta and neurofibrillary tangles lead to the cause of Alzheimer’s disease.

More specifically, the Tau hypothesis proposes that tau protein abnormalities initiate the disease cascade where hyperphosphorylated tau begins to combine with other threads of tau and they eventually form neurofibrillary tangles inside the neuron.  As a result of this process, the microtubules disintegrate which destroys the neuron’s cytoskeleton.  With the destruction of the neuron’s cytoskeleten, the neuron’s transportation system is collapsed. 

When the neuron’s transportation system collapses, a malfunction in the biochemical communication between neuron’s occur.  Ultimately this results in the death of the neuron.  Amyloid beta plaques do not correlate with neuron loss.

The abnormal aggregation of the tau protein defines Alzheimer’s disease as a tauopathy.  Tauopathy is defined as a class of neurodegenerative diseases in which pathological aggregation of tau protein in neurofibrillary or gliofibrillary tangles occur in the human brain.

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The tau hypothesis of Alzheimer’s disease progression

NFT: Neurofibrillary tangles; PHF: Paired helical filaments.

Source:  Advances in Tau-focused drug discovery for Alzheimer’s disease and related tauopathies

A number of therapeutic strategies have been proposed and focuses on targeting the decrease of the microtubule-associated protein tau.  These include:  3

  • controlling tau degradation via chaperones
  • enhance tau clearance
  • inhibiting formation of tau aggregates
  • preventing tau aggregation
  • regulating tau using kinases
  • stabilizing tau microtubules

Scientists have identified a number of natural compounds that have potential in inhibiting or reducing the levels of the tau protein.  The Table below lists some of these identified natural compounds with the abstracts and citation to the various studies:

Natural Compounds as Potential Therapeutic Agents for Inhibiting and Decreasing Tau Protein

Aged garlic (Allium sativum)Current study investigated anti-amyloidogenic, anti-inflammatory and anti-tangle effects of dietary aged garlic extract (AGE) (2%) and compared with its prominent constituents, i.e. S-allyl-cysteine (SAC) (20 mg/kg) and di-allyl-disulfide (DADS) (20 mg/kg) in Alzheimer's Swedish double mutant mouse model (Tg2576).1
Bayberry root bark (Myrica cerifera)The bayberry flavonoids myricetin and myricitrin were confirmed to contribute to this potency, but a diarylheptanoid, myricanol, was the most effective anti-tau component in the extract, with potency approaching the best targeted lead therapies. (+)-aR,11S-Myricanol, isolated from M. cerifera and reported here for the first time as the naturally occurring aglycone, was significantly more potent than commercially available (±)-myricanol. Myricanol may represent a novel scaffold for drug development efforts targeting tau turnover in AD.2
Chinese Yew, Taxus yunnanensisThe stimulatory and inhibitory effects of several compounds and lignans isolated from the water extract of Taxus yunnanensis on the phosphorylation of three functional brain proteins (bovine myelin basic protein (bMBP), recombinant human tau protein (rhTP) and rat collapsin response mediator protein-2 (rCRMP-2)) by glycogen synthase kinase-3β (GSK-3β) were quantitatively compared in vitro3
Cinnamon (Cinnamonium zeylanicum)An aqueous extract of Ceylon cinnamon (C. zeylanicum) is found to inhibit tau aggregation and filament formation, hallmarks of Alzheimer's disease (AD). The extract can also promote complete disassembly of recombinant tau filaments and cause substantial alteration of the morphology of paired-helical filaments isolated from AD brain. Cinnamon extract (CE) was not deleterious to the normal cellular function of tau, namely the assembly of free tubulin into microtubules.4
CurcuminFollowing a six-month prevention period where mice received extract HSS-888 (5mg/mouse/day), tetrahydrocurcumin (THC) or a control through ingestion of customized animal feed pellets (0.1% w/w treatment), HSS-888 significantly reduced brain levels of soluble (~40%) and insoluble (~20%) Aβ as well as phosphorylated Tau protein (~80%).5
Emodin (Japanese Knotweed - Fallopia japonica)Here we demonstrate the feasibility of the approach with several compounds from the family of anthraquinones, including emodin, daunorubicin, adriamycin, and others. They were able to inhibit PHF formation with IC50 values of 1-5 microm and to disassemble preformed PHFs at DC50 values of 2-4 microm. The compounds had a similar activity for PHFs made from different tau isoforms and constructs. The compounds did not interfere with the stabilization of microtubules by tau.6
Fulvic Acid/Humic Acid (Shilajit)Fulvic acid, a humic substance, has several nutraceutical properties with potential activity to protect cognitive impairment. In this work we provide evidence to show that the aggregation process of tau protein, forming paired helical filaments (PHFs) in vitro, is inhibited by fulvic acid affecting the length of fibrils and their morphology. In addition, we investigated whether fulvic acid is capable of disassembling preformed PHFs. We show that the fulvic acid is an active compound against preformed fibrils affecting the whole structure by diminishing length of PHFs and probably acting at the hydrophobic level, as we observed by atomic force techniques. Thus, fulvic acid is likely to provide new insights in the development of potential treatments for Alzheimer's disease using natural products.7
Ginsenoside RdThe result of the present work implied that ginsenoside Rd protected SD rats and cultured cortical neurons against OA-induced toxicity. The possible neuroprotective mechanism may be that ginsenoside Rd decreases OA-induced the hyperphosphorylation of tau by the increase in activities of PP-2A. Thus, this study promises that ginsenoside Rd might be a potential preventive drug candidate for AD and other tau pathology-related neuronal degenerative diseases.8
Grape seed (Vitis vinifera)Recent studies from our laboratory reveal that grape seed-derived polyphenolic extracts (GSPE) potently prevent tau fibrillization into neurotoxic aggregates and therapeutically promote the dissociation of preformed tau aggregates9 10
Green tea (Camellia sinensis)Several phenothiazines (methylene blue, azure A, azure B, and quinacrine mustard), polyphenols (myricetin, epicatechin 5-gallate, gossypetin, and 2,3,4,2',4'-pentahydroxybenzophenone), and the porphyrin ferric dehydroporphyrin IX inhibited tau filament formation with IC(50) values in the low micromolar range as assessed by thioflavin S fluorescence, electron microscopy, and Sarkosyl insolubility.11
MyricetinPolyphenols such as Curcumin, Exifone, and Myricetin exhibit modest inhibition toward fibril formation of tau peptide which is associated with Alzheimer's disease.12
Oleocanthal from olive oil (Oleaeuropaea)Since our unpublished data indicates an inhibitory effect of oleocanthal on Aβ fibrillization, we reasoned that it might inhibit tau fibrillization as well. Herein we demonstrate that oleocanthal abrogates fibrillization of tau by locking tau into the naturally unfolded state.13
Red sage (Salvia miltiorrhiza)The results showed that Tanshinone IIA (tanIIA), protected neurons against the neurotoxicity of Aβ(25-35), increased the viability of neurons, decreased expression of phosphorylated tau in neurons induced by Aβ(25-35), improved the impairment of the cell ultrastructure (such as nuclear condensation and fragmentation, and neurofibril collapse).14
Sage (Salvia offinalis)In this study, we evaluated the effect of a standardized extract from the leaves of sage (Salvia officinalis) and its active ingredient, rosmarinic acid (12), which reduced tau hyperphosphorylation in addition to attenuating several Alzheimer’s disease pathways, such as reactive oxygen species formation, lipid peroxidation, DNA fragmentation, caspase-3 activation and amyloid beta accumulation15

Certain Spices Inhibit Beta Secretase Which Slow Accumulation Of Amyloid Beta

Amyloid beta, the principal component of senile plaques, is thought to be the pathogenesis of Alzheimer’s disease.  The development of Alzheimer’s disease is associated with plaques and tangles in the brain.  These plaques and tangles are referred to as amyloids which are aggregates of proteins that become folded into a shape that allows many copies of that protein to stick together.  The amyloid-cascade hypothesis states that the production and excessive accumulation of amyloid beta is the primary pathological event leading to Alzheimer’s disease.  1

The precursor to amyloid beta is Amyloid Precursor Protein (APP), which is endogenous in brain cells and is inert.  The inert APP is converted by proteolytic enzymes by being cleaved by proteases in the secretase family, namely:  2

One of these three secretase enzymes is beta secretase (or BACE1).  The initial stage of cleaving APP is done by beta secretase. 

Thus a therapeutic strategy for Alzheimer’s disease is to inhibit over expression beta secretase.

A study from 2015 published in the Journal of Natural Medicines focused on the inhibition of beta-secretase from plant resources including herbs and spices.  The researchers screened a number of herbs and spices for their ability to inhibit beta secretase.   They discovered a number of chemical compounds found in a number of spices that were effective in inhibiting beta secretase.  These chemical compounds include:  3

  • alpha-caryophyllene
  • beta-caryophyllene
  • beta-caryophyllene oxide
  • curcumin
  • demethoxycurcumin
  • bisdemethoxycurcumin
  • piperine

Since the molecular weight of these chemical compounds are relatively low, they are able to pass through the blood brain barrier and effect their therapeutic value.

The study identified the spices that contain these 7 chemical compounds, although they are found in other herbs and spices:

Spices Containing Beta Secretase Inhibiting Chemical Compounds

Chemical CompoundSpice
alpha-caryophylleneblack pepper
beta-caryophyllene black pepper
beta-caryophyllene oxidecurry leaf
curcumintumeric root
demethoxycurcumintumeric root
bisdemethoxycurcumintumeric root
piperineblack pepper
Source: DOI: 10.1007/s11418-014-0859-3

Additional information on the 7 chemical compounds:


Alpha-caryophyllene, also known as Humulene or alpha-humulene is a naturally occurring monocyclic sesquiterpene that was first found in the essential oils of Humulus lupulus (hops). Alpha-caryophyllene is an isomer of Beta-caryophyllene and both are of found together in aromatic plants.

Alpha-caryophyllene is contained in the essential oils of aromatic plants such as Salvia officinalis (common sage, culinary sage), ginseng species. It is also the characteristic aroma of Cannabis sativa, an interestingly is was shown to be a selective agonist of cannabinoid receptor type-2 (CB2). 1


Beta-caryophyllene is a natural bicyclic sesquiterpene that is a constituent of many essential oils.  It provides the spiciness to black pepper.

The approximate quantity of caryophyllene in the essential oil of each source is given in square brackets ([ ]):

  • Basil (Ocimum spp.) [5.3–10.5% O. gratissimum; 4.0–19.8% O. micranthum]
  • Black caraway (Carum nigrum) [7.8%]
  • Black pepper (Piper nigrum) [7.29%]
  • Cannabis, hemp, marijuana (Cannabis sativa) [3.8–37.5% of cannabis flower essential oil]
  • Cloves (Syzygium aromaticum) [1.7%-19,5% of clove bud essential oil]
  • Copaiba oil (Copaifera spp.)
  • Hops (Humulus lupulus) [5.1–14.5%]
  • Lavender (Lavandula angustifolia) [4.62% of lavender oil]
  • Malabathrum (Cinnamomum tamala) [25.3%]
  • Oregano (Origanum vulgare) [4.9%-15.7]
  • Rosemary (Rosmarinus officinalis) [0.1–8.3%]
  • True cinnamon (Cinnamomum zeylanicum) [6.9–11.1%]
  • Ylang-ylang (Cananga odorata) [3.1%-10.7%]

Source: Wikipedia - Caryophyllene

beta-caryophyllene oxide

Caryophyllene oxide is similar in structure to beta-caryophyllene and its function in plants is to act as a defence against disease causing microbes, especially fungal microbes.  It is found in in lemon balm (Melissa officinalis) as well as curry leaf (Murraya koenigii (L.) Spreng).

Curry leaf is not the same as curry.  Curry is a complex combinations of spices or herbs, usually including fresh or dried hot chillies, coriander, cumin, and turmeric.  Curry leaf is from the curry tree (Murraya koenigii or Bergera koenigii) and is native to India and Sri Lanka.

Curry leaf contains up to 58 compounds of which the major one is caryophyllene oxide at 16.6%.   1

curcumin, demethoxycurcumin, bisdemethoxycurcumin

Tumeric root contains four curcuminoids, which is the main active ingredients:

  • bisdemethoxycurcumin
  • curcumin
  • cyclocurcumin
  • demethoxycurcumin

Most commercial available preparations of “curcumin” contain approximately 77% curcumin, 17% demethoxycurcumin and 3% bisdemethoxycurcumin. 1

Curcuminoids primarily exist in the curcuma genus with the highest amounts in curcuma longa (tumeric root).  Cucuminoids also exit in Ginger (Zingiber officinale).


Piperine is found in a number of species in the genus Piper.  It is an alkaloid that is responsible for the pungency of black pepper and long pepper.

Images of the 3 Spices and their chemical constituients that inhibit beta secretase

  • Black Pepper (alpha-caryophyllene, beta-caryophyllene and piperine)

Cover Photo:  Curry Tree (Murraya koenigii (L.) Spreng)