Category Archives: Neurological

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Consuming Extra Virgin Olive Oil could be a Viable Therapeutic Opportunity for Preventing or Halting Dementia and Alzheimer’s Disease

Researchers from the Lewis Katz School of Medicine at Temple University (LKSOM) published a study online on June 21, 2017 in the Annals of Clinical and Translational Neurology which identifies extra virgin olive oil (EVOO) as protective against cognitive decline.  1

The consumption of EVOO shows great promise against the classic markers of dementia and Alzheimer’ disease.  What this new study demonstrated where the following discoveries from EVOO:

  • Reduces neuro-inflammation
  • Activates autophagy
  • Restores and protects working and spatial memory and learning ability 
  • Reduces the formation of amyloid-beta plaques
  • Reduces the formation of neurofibrillary tangles from phosphorylated tau
  • Does not effect CREB signaling

In this study, the researchers used a well-established Alzheimer’s disease mouse model known as triple transgenic mice (3xTg).

Triple transgenic mice (3xTg) contain three mutations associated with familial Alzheimer’s disease:

  • APP Swedish
  • MAPT P301L
  • PSEN1 M146V

Image result for Triple transgenic mice

Figure 1. Triple transgenic mouse model.   (Source)

Due to these mutations, these mice develop the three characteristics of Alzheimer’s disease, namely:

  • amyloid plagues
  • memory impairment
  • neurofibrillary tangles

The mice are viable, fertile, and display no initial gross physical or behavioral abnormalities. These mice display both plaque and tangle pathology.

Amyloid beta deposition is progressive, with intracellular immunoreactivity detected in some brain regions as early as three to four months of age. Extracellular Amyloid beta deposits appear by six months in the frontal cortex and become more extensive by twelve months.

Changes in tau occur later; by 12 to 15 months aggregates of conformationally-altered and hyper-phosphorylated tau are detected in the hippocampus.  2  

The researchers feed two groups of triple transgenic mice, a group that received a chow diet with EVOO starting at 6 months of age for a period of 6 months, and the other group as a control group that received no EVOO enhanced chow.  At 6 months of age is when there are no symptoms of Alzheimer’s disease in the triple transgenic mice.

At 9 months of age, the researchers started to assess the effect of the diet on Alzheimer’s disease neuropathology and behavioral changes.

At 9 and 12 months of age, the researchers observed that the group on the EVOO enriched chow diet improved cognitive function and and found that the Alzheimer’s markers were improved.

Specifically, the researchers found six discoveries from their experiment on the triple transgenic mice fed the EVOO enriched diet:

EVOO-rich diet restores working and spatial memory in 3xTg mice

The mice were tested at age of 9 and 12 months in the Y-maze.  The mice at 9 and 12 months showed a reduction in the number of entries that reached the statistical significance for the control (non-EVOO diet) group at 9 months.  When the researchers assessed the percentage of alternation, they observed a reduction of this parameter in the control group at both 9 and 12 months but, this was completely rescued in the EVOO treated mice.

EVOO-rich diet reduces Amyloid beta levels and deposition in 3xTg mice

At 12 months of age, mice were euthanized and brain cortex homogenates was assayed for amyloid beta levels in the RIPA-soluble and formic acid-soluble fractions. Compared with controls, we found that EVOO group presented a decrease in amyloid beta1-40 levels that reached the statistical significance.

EVOO-rich diet attenuates tau pathology

Phosphorylated tau is responsible for neurofibrillary tangles, which are suspected of contributing to the nerve cell dysfunction in the brain that is responsible for Alzheimer’s memory symptoms.

The researchers found a significant reduction in the phosphorylated forms of tau at Ser202/Thr205 and Ser396/Ser404, as recognized by the antibodies AT8 and PHF13, respectively, in the EVOO group when compared with mice on a regular diet (control group).

EVOO-rich diet improves synapse integrity and neuro-inflammation

To assess whether the improved cognitive performance and Alzheimer’s disease pathology seen in the EVOO-treated mice was also biochemically characterized by an amelioration of synaptic integrity, we assayed the steady state levels of two major synaptic proteins: synaptophysin (SYP) indices of presynaptic integrity, and the postsynaptic density protein 95 (PSD95).

No differences were observed between the two groups when PSD95 levels were measured. By contrast, mice fed with EVOO-rich diet when compared with the control group, displayed a statistically significant increase in the steady state levels of SYP.

EVOO-rich diet does not affect CREB signaling on 3xTg mice

CREB (cAMP response element-binding protein) is a cellular transcription factor which binds to certain DNA sequences called cAMP response elements (CRE), thereby increasing or decreasing the transcription of the downstream genes.

CREB has a well-documented role in neuronal plasticity and long-term memory formation in the brain and has been shown to be integral in the formation of spatial memory.  CREB downregulation is implicated in the pathology of Alzheimer’s disease and increasing the expression of CREB is being considered as a possible therapeutic target for Alzheimer’s disease.

The researchers investigated the effect of our EVOO-rich diet on total CREB levels and its phosphorylated form at Ser133 (p-CREB). The levels of total CREB and p-CREB were not changed in the brain of EVOO-treated mice compared to controls. Additionally, no differences were detected in the protein expression level of BDNF and cFos, two important CREB target genes, between the two groups

EVOO-rich diet induces autophagy in 3xTg mice

Autophagy is the process by which cells break down and clear out intracellular debris and toxins, such as amyloid plaques and tau tangles.  It is often thought that a reduction in autophagy marks the beginning of Alzheimer’s disease.

Finally, the researchers looked at several autophagy markers, including ATG5-12, ATG7 and the microtubule-associated protein light chain 3 conversion (LC3I/II) which are considered essential for the autophagosome formation and autophagic flux, respectively.  In this study, ATG5 and ATG7 immunoreactivity was significantly stronger in EVOO-treated mice compared to controls suggesting induction of autophagy in this group of 3xTg mice.

The researchers had a very favorable conclusion as it related to the consumption of EVOO and its prevention of dementia and Alzheimer’s disease.  They stated:

“In conclusion, our investigation establishes for the first time to the best of our knowledge a protective effect of EVOO in modulating tau phosphorylation, memory impairments, synaptic integrity, and neuro-inflammation in a mouse model of AD with plaques and tangles.

The translational value of our findings lies in the observation that EVOO supplementation can influence the entire spectrum of the AD phenotype. Our studies provide mechanistic support to the positive cross-sectional and longitudinal data on this component of the Mediterranean diet, and most importantly the biological rationale to the novel hypothesis that EVOO could be considered as a viable therapeutic opportunity for preventing or halting AD.”  3

Extra Virgin Olive Oil

It is important to note that the olive oil used in this study was a high phenolic content EVOO. High phenolic EVOO contains a higher number of polyphenols and a higher percentage of those polyphenols than regular EVOO. 

EVOO contains many polyphenols, at least up to thirty.  The more important polyphenols in EVOO include:

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

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 or higher.  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.

A superior and exceptional EVOO with a very high phenolic content is The Governor™, which is grown and produced on the island of Corfu, Greece.

Figure 2.  The Governor™ Premium variety  (Copyright The Governor™)

The Governor™ has two varieties:

  • The Governor™ Premium
  • The Governor™ Limited

The Governor™ was scientifically tested in March 2014 at the University of Athens and compared with the results of 700 other olive oil samples, from 30 different olive varieties. 150 of the comparative olive oil samples originated from countries outside Greece, specifically: California, Italy, Spain, Croatia, Tunisia, Cyprus, France, Argentina, Chile, Morocco and Israel.

The results were impressive. The oleocanthal and oleacein concentrations in The Governor™ are 7 times higher than the average of the samples and the highest value recorded among all commercially-available bottled oils since 2009.

Oleocanthal, oleocein and other elements present in The Governor™ olive oil present important biological activity, and are related with anti-inflammatory, antioxidant and neuro-protective benefits.

The total hydroxytyrosol derivatives are 61% higher than the stipulated European regulation.

Prokopis Magiatis, Associate Professor at the Athens University Faculty of Pharmacy commented on The Governor™ EVOO:

“..we can certify that [“The Governor”™] is an extremely rare extra virgin olive oil that stands out from the usual oils… It is an oil highly recommended to all consumers looking for olive oil with enhanced properties for health protection.”

The Governor™ website can be viewed here.

The Governor™ EVOO can be bought online from various sources, including:

Olympic Trading, Co.

Elenianna

Amazon

Olympicco

Repairing the Damaged Plasma Membrane of the Cell and the Membrane-Bound Organelles

Introduction to the Plasma Membrane

The human cell is enveloped in a thin, pliable, elastic structure called the cell membrane or the plasma membrane and is only 7.5 to 10 nanometers thick. It is composed almost entirely of proteins and lipids.  There are approximately 5 × 106 lipid molecules in a 1 μm × 1 μm area of lipid bilayer, or about 109 lipid molecules in the plasma membrane of a human cell.

The main purpose of the plasma membrane is to separate the inner contents of the cell from its exterior environment, much like the outer layer of the skin separates the body from its environment.  In addition to providing a protective barrier around the cell, the plasma membrane regulates which materials pass in and out of the cell.

The plasma membrane envelops the human cell and is also found inside the cell in various intracellular membranes, called organelles.  The structure and composition of the plasma membrane are the same for the plasma membrane surrounding the cell as well as for the various intracellular membranes.  The only difference among them is the proportions which vary from one type of membrane to the other.

The formation of plasma membranes is based on the structural organization of bilayers of lipids with associated proteins.  The lipid content of the plasma membrane ranges from 40 to 80% (of dried weight), which is significant.  The two main lipids that predominate quantitatively in the lipid fraction of the plasma membrane are:

  • phosphatidylcholine
  • phosphatidylethanolamine

The lipid molecules in plasma membranes are amphipathic (or amphiphilic)—that is, they have a hydrophilic (“water-loving”) or polar end and a hydrophobic (“water-fearing”) or nonpolar end.

Functions of the Plasma Membrane

In addition to the plasma membrane providing a protective barrier around the cell and the intracellular organelles, it has many essential functions:

  • transporting nutrients into the cell
  • transporting metabolic wastes out of the cell
  • preventing unwanted materials in the extracellular milieu from entering the cell
  • preventing loss of needed metabolites
  • maintaining the proper ionic composition, pH (≈7.2), and osmotic pressure of the cytosol
  • provides cell to cell communication
  • provides hormone sensitivity and utilization
  • support the many enzymatic reactions that occur along their surfaces

These various functions are carried out by specific transport proteins which restrict the passage of certain small molecules.

The plasma membrane actually has a measurable membrane differential which is the voltage across the plasma membrane.  It has been determined that healthy children has a membrane electrical potential up to 90 millivolts, whereas a healthy adult can have up to 70 millivolts.  The membrane electrical potential can decline to around 40 millivolts in an individual with a chronic disease and to as low as 15 millivolts in an individual with advanced cancer.

The Lipids Comprising the Plasma Membrane of the Human Cell

The plasma membrane of the human cell and certain intracellular organelles inside the cell are composed of three categories of lipids:

  • Phospholipids (Glycerophospholipids or Phospholycolipids or Phosphoglycerides and Phosphosphingolipids)
  • Glycolipids
  • Cholesterol

Of the three categories of  lipids, the most abundant membrane lipids are the phospholipids.

The functions of the plasma membrane determines the lipid compositions of the inner and outer monolayers of the cell plasma membrane.  Different mixtures of lipids are found in the membranes of cells of different types.  The two sides of the plasma membrane of the human cell reflect this difference:

Outer Layer (the side on the exterior of the cell)

Consists mainly of phosphatidylcholine and sphingomyelin

Inner Layer (the side on the interior of the cell)

Consists mainly of phosphatidylethanolamine and phosphatidylserine and phosphatidylinositol.  

Figure 12.2. Lipid components of the plasma membrane.

Figure 1.  Lipid components of the plasma membrane

The outer leaflet consists predominantly of phosphatidylcholine, sphingomyelin, and glycolipids, whereas the inner leaflet contains phosphatidylethanolamine, phosphatidylserine, and phosphatidylinositol. Cholesterol is distributed in both leaflets. The net negative charge of the head groups of phosphatidylserine and phosphatidylinositol is indicated. (Source:  The Cell: A Molecular Approach. 2nd edition., The Molecular Composition of Cells)

The mitochondria, an intracellular organelle, contains two membranes and consists primarily of phosphatidylcholine, phosphatidylethanolamine, phosphatidylinositol, phosphatidylserine, and phosphatidic acid.  These phospholipids are asymmetrically distributed between the two halves of the membrane bilayer of the mitochondria.  The inner mitochondrial membrane contains a specific phospholipid called phosphatidylglycerol and is the precursor for cardiolipin.  Cardiolipin is predominantly found in the inner mitochondrial membrane.

Lipids constitute approximately 50% of the mass of most cell membranes, although this proportion varies depending on the type of membrane. Plasma membranes, for example, are approximately 50% lipid and 50% protein.

The lipid composition of different cell membranes also varies:

  Plasma membrane    
Lipid E. coli Erythrocyte Rough endoplasmic reticulum Outer mitochondrial membranes
Phosphatidylcholine 0 17 55 50
Phosphatidylserine 0 6 3 2
Phosphatidylethanolamine 80 16 16 23
Sphingomyelin 0 17 3 5
Glycolipids 0 2 0 0
Cholesterol 0 45 6 <5

Membrane compositions are indicated as the mole percentages of major lipid constituents.

Another source lists the lipid compositions of different cell membranes:

  PERCENTAGE OF TOTAL LIPID BY WEIGHT
LIPID LIVER CELL PLASMA MEMBRANE RED BLOOD CELL PLASMA MEMBRANE MYELIN MITOCHONDRION (INNER AND OUTER MEMBRANES) ENDOPLASMIC RETICULUM E. COLIBACTERIUM
Cholesterol 17 23 22 3 6 0
Phosphatidylethanolamine 7 18 15 25 17 70
Phosphatidylserine 4 7 9 2 5 trace
Phosphatidylcholine 24 17 10 39 40 0
Sphingomyelin 19 18 8 0 5 0
Glycolipids 7 3 28 trace trace 0
Others 22 13 8 21 27 30
(Source: Molecular Biology of the Cell. 4th edition., The Lipid Bilayer; Alberts B, Johnson A, Lewis J, et al. New York: Garland Science; 2002.)
Phospholipids that Compose the Plasma Membrane

Plasma membranes contain 4 major and 1 minor phospholipids:

  • Major phospholipids
    • phosphatidylcholine
    • phosphatidylethanolamine
    • phosphatidylserine
    • sphingomyelin
  • Minor phospholipids
    • phosphatidylinositol

These major phospholipids together account for more than 50% of the lipid in most membranes. Phosphotidylinositol is present in smaller quantities in the plasma membrane but provide important functions like cell signaling.

  Figure 10-12. Four major phospholipids in mammalian plasma membranes.

Figure 2.  Four major phospholipids in mammalian plasma membranes

Note that different head groups are represented by different colors. All the lipid molecules shown are derived from glycerol except for sphingomyelin, which is derived from serine.  (Source: Molecular Biology of the Cell. 4th edition., The Lipid Bilayer; Alberts B, Johnson A, Lewis J, et al. New York: Garland Science; 2002.)

Phosphatidylcholine

Phosphatidylcholine is a vital substance found in every cell of the human body.

Phosphatidylethanolamine

Phosphatidylethanolamines are found in all living cells, composing 25% of all phospholipids. In humans, they are found particularly in nervous tissue such as the white matter of brain, nerves, neural tissue, and in spinal cord, where they make up 45% of all phospholipids.  1

Phosphatidylserine

Phosphatidylserine is a component of the cell membrane. It plays a key role in cell cycle signaling, specifically in relationship to apoptosis.  

Sphingomyelin

Sphingomyelin is a type of sphingolipid found in animal cell membranes, especially in the membranous myelin sheath that surrounds nerve cell axons. It usually consists of phosphocholine and ceramide, or a phosphoethanolamine head group; therefore, sphingomyelins can also be classified as sphingophospholipids.

Phosphatidylinositol (minor phospholipid)

Phosphatidylinositol forms a minor component on the cytosolic side of eukaryotic cell membranes.

Phosphorylated forms of phosphatidylinositol are called phosphoinositides and play important roles in lipid signaling, cell signaling and membrane trafficking.

Phosphatidylglycerols  (Cardiolipin)

Phosphatidic acid reacts with CTP, producing CDP-diacylglycerol, with loss of pyrophosphate. Glycerol-3-phosphate reacts with CDP-diacylglycerol to form phosphatidylglycerol phosphate, while CMP is released. The phosphate group is hydrolysed forming phosphatidylglycerol.

Two phosphatidylglycerols form cardiolipin, the constituent molecule of the mitochondrial inner membrane.  2

Phosphatidic acid

Phosphatidic acids are the acid forms of phosphatidates, a part of common phospholipids, major constituents of cell membranes.  phosphatidic acids are the simplest diacyl-glycerophospholipids.

The role of phosphatidic acid in the cell can be divided into three categories:

  • Phosphatidic acid is the precursor for the biosynthesis of many other lipids
  • The physical properties of phosphatidic acid influence membrane curvature
  • Phosphatidic acid acts as a signaling lipid, recruiting cytosolic proteins to appropriate membranes

The conversion of phosphatidic acid into diacylglycerol (DAG) by LPPs is the commitment step for the production of phosphatidylcholine, phosphatidylethanolamine and phosphatidylserine. In addition, DAG is also converted into CDP-DAG, which is a precursor for phosphatidylglycerol, phosphatidylinositol and phosphoinositides.

Phosphatidic acid is essential for lipid synthesis and cell survival, yet, under normal conditions, is maintained at very low levels in the cell.

Glycolipids

The role of glycolipids is to maintain stability of the membrane and to facilitate cellular recognition.  3 

Carbohydrates are found on the outer surface of all eukaryotic cell membranes. They extend from the phospholipid bilayer into the aqueous environment outside the cell where it acts as a recognition site for specific chemicals as well as helping to maintain the stability of the membrane and attaching cells to one another to form tissues.

Figure 3.  Glycolipid attached to lipid residue

The lipid complex is most often composed of either a glycerol or sphingosine backbone, which gives rise to the two main categories of glycolipids:

  • glyceroglycolipids
  • sphingolipids

The heads of glycolipids contain a sphingosine with one or several sugar units attached to it. The hydrophobic chains belong either to:

  • two fatty acids – in the case of the phosphoglycerides, or
  • one fatty acid and the hydrocarbon tail of sphingosine – in the case of sphingomyelin and the glycolipids

Glycolipids occur in all animal cell plasma membranes, where they generally constitute about 5% of the lipid molecules in the outer monolayer. They are also found in some intracellular membranes.

The most complex of the glycolipids, the gangliosides, contain oligosaccharides with one or more sialic acid residues, which give gangliosides a net negative charge.  More than 40 different gangliosides have been identified. They are most abundant in the plasma membrane of nerve cells, where gangliosides constitute 5–10% of the total lipid mass; they are also found in much smaller quantities in other cell types.

Cholesterol

Cholesterol is a sterol, and is biosynthesized by all animal cells, and is an essential structural component of all animal cell membranes; essential to maintain both membrane structural integrity and fluidity. Cholesterol enables animal cells to dispense with a cell wall (to protect membrane integrity and cell viability), thereby allowing animal cells to change shape and animals to move (unlike bacteria and plant cells, which are restricted by their cell walls).

Cell membranes require high levels of cholesterol – typically an average of 20% cholesterol in the whole membrane, increasing locally in raft areas up to 50% cholesterol.  4 

Within the cell membrane, cholesterol also functions in intracellular transport, cell signaling and nerve conduction. Recent studies show that cholesterol is also implicated in cell signaling processes, assisting in the formation of lipid rafts in the plasma membrane, which brings receptor proteins in close proximity with high concentrations of second messenger molecules.  5  

In multiple layers, cholesterol and phospholipids, both electrical insulators, can facilitate speed of transmission of electrical impulses along nerve tissue. For many neuron fibers, a myelin sheath, rich in cholesterol since it is derived from compacted layers of Schwann cell membrane, provides insulation for more efficient conduction of impulses.  6 

Figure 2.47. Insertion of cholesterol in a membrane.

Figure 4.  Insertion of cholesterol in a membrane

Cholesterol inserts into the membrane with its polar hydroxyl group close to the polar head groups of the phospholipids.

Organelles of the Human Cell

An organelle is a specialized sub-unit within a cell that serves a specific function.  Most organelles of the cell are covered by membranes composed primarily of lipids and proteins.

Organelles either have a single-membrane compartment or a double-membrane compartment. 

There are 10 organelles in the human cell that have either a single or double membrane.  There are 3 organelles with double membranes and 7 organelles with single membranes.  The organelles of the cell with membranes are as follows:

Organelle

Function

Membrane Structure

Autophagosome

vesicle that sequesters cytoplasmic material and organelles for degradation

Double membrane

Endoplasmic reticulum

translation and folding of new proteins (rough endoplasmic reticulum), expression of lipids (smooth endoplasmic reticulum)

Single membrane

Golgi apparatus

sorting, packaging, processing and modification of proteins

Single membrane

Lysosomes

breakdown of large molecules (e.g., proteins + polysaccharides)

Single membrane

Melanosome

pigment storage

Single membrane

Mitochondria

energy production from the oxidation of glucose substances and the release of adenosine triphosphate

Double membrane

Nucleus

DNA maintenance, controls all activities of the cell, RNA transcription

Double membrane

Peroxisome

breakdown of metabolic hydrogen peroxide

Single membrane

Vacoule

storage, transportation, helps maintain homeostasis

Single membrane

Vesicle

material transport

Single membrane

Organelles with double membranes are often critical to the function of the cell, each serveing a different purpose.  There are 3 organelles that have double membranes:

  • Mitochondria

  • Nucleus

  • Autophagosome

Mitochondria

A mitochondrion (singular for mitochondria) contains outer and inner membranes composed of phospholipid bilayers and proteins.   Due to the double membrane structure of the mitochondrion, there are five distinct parts to a mitochondrion. They are:

  • the outer mitochondrial membrane
  • the intermembrane space (the space between the outer and inner membranes)
  • the inner mitochondrial membrane
  • the cristae space (formed by infoldings of the inner membrane)
  • the matrix (space within the inner membrane)

The mitochondrial membrane contains the major classes of phospholipids found in all cell membranes, including phosphatidylcholine, phosphatidylethanolamine, phosphatidylinositol, phosphatidylserine, and phosphatidic acid, as well as phosphatidylglycerol, the precursor for cardiolipin; which is predominantly located in the mitochondria.

The outer mitochondrial membrane, which encloses the entire organelle, has a protein-to-phospholipid ratio similar to that of the human plasma membrane (about 1:1 by weight). It contains large numbers of integral membrane proteins called porins.

In the inner mitochondrial membrane, the protein-to-lipid ratio is 80:20, in contrast to the outer membrane, which is 50:50.  7 

The inner membrane is rich in cardiolipin.  Cardiolipin contains four fatty acids rather than two, and may help to make the inner membrane impermeable.  Unlike the outer membrane, the inner membrane doesn’t contain porins, and is highly impermeable to all molecules.

Nuclear Membrane

The nuclear envelope, otherwise known as nuclear membrane, consists of two cellular membranes, an inner and an outer membrane, arranged parallel to one another and separated by 10 to 50 nanometres (nm). The nuclear envelope completely encloses the nucleus and separates the cell’s genetic material from the surrounding cytoplasm, serving as a barrier to prevent macromolecules from diffusing freely between the nucleoplasm and the cytoplasm. 8   The outer nuclear membrane is continuous with the membrane of the rough endoplasmic reticulum.

Autophagosome

An autophagosome is a spherical structure with double layer membranes. It is the key structure in macro autophagy, the intracellular degradation system for cytoplasmic contents (e.g., abnormal intracellular proteins, excess or damaged organelles) and also for invading microorganisms.

After formation, autophagosomes deliver cytoplasmic components to the lysosomes. The outer membrane of an autophagosome fuses with a lysosome to form an autolysosome. The lysosome’s hydrolases degrade the autophagosome-delivered contents and its inner membrane.  9

Damage and Degradation to the Cell Membrane

When cell membranes are intact their receptor surface is able to perform all necessary functions. Communication between cells, and even within the cell components, flows easily. Once the membrane is damaged this communication is disrupted, and the cell cannot function properly, due to the failure of cellular signaling. 

There are a number ways in which cell membranes can be damaged, which eventually leads to pathology and illness.  This is true of both the cell and its outer membrane barrier or cell membrane, and the membrane structures inside the cell.  Various factors can contribute to damage to the cell membrane, such as:

  • Acetaldehyde
  • Aging
  • Alcohol
  • Excessive Saturated Fatty Acids
  • Lipid peroxidation
  • Oxidization of cell membrane
  • Recreational Drugs
  • Smoking
  • Toxin exposure (toxins stored in the lipid environment)
  • Trans-fatty acids  10  11

Aging causes detrimental changes in membrane phospholipid composition. Phosphatidylcholine is one of the main types of phospholipids in the cell membrane, and its concentration within the cell membrane decreases with age, whereas sphingomyelin and cholesterol both increase with age. 

The changes in the relative amounts of phosphatidylcholine and sphingomyelin are especially great in tissues. Plasma membranes associated with the aorta and arterial wall show a 6-fold decrease in phosphatidylcholine and sphingomyelin ratio with aging. Sphingomyelin also increases in several diseases, including atherosclerosis. The sphingomyelin content can be as high as 70-80% of the total phospholipids in advanced aortic lesion.  12  

Decreased cell membrane fluidity and decomposition of cell membrane integrity, as well as break down of cell membrane repair mechanisms, are associated with various disorders, including liver disease, atherosclerosis, several cancers and ultimately cell death.

Fatty acids within the cell membrane degrade when dietary fats are either oxidized (lipid peroxides can form within the body as well) or contain trans fatty acids.

Plasma membranes are one of the preferential targets of reactive oxygen species which cause lipid peroxidation. This process modifies membrane properties such as fluidity, a very important physical feature known to modulate membrane protein localization and function.  13  

Numerous reports have established that lipid peroxidation contributes to cell injury by altering the basic physical properties and structural organization of membrane components. Oxidative modification of polyunsaturated phospholipids has been shown, in particular, to alter the intermolecular packing, thermodynamic, and phase parameters of the membrane bilayer.  14  15

Damage to the Double Membrane Structure of the Mitochondria

Damage to mitochondrial components, especially the delicate inner mitochondrial membrane, leads to the release of toxic proteins, including caspases and other enzymes. These proteins are normally confined in the mitochondria, but once released these proteins go through several steps that trigger the formation of a potent inflammatory molecular complex called an inflammasome.

New evidence has placed inflammasomes at the center stage of complex diseases like metabolic syndrome and cancer, as well as the regulation of the microbial ecology in the intestine and the production of ATP.  16 

Once the inner membrane of the mitochondria is damaged, its core ability to produce energy in the form of ATP and to maintain optimal mitochondrial nutrient uptake and utilization necessary for ATP production are impaired.

The inner mitochondrial membrane is also one of the most sensitive membranes of the cell to oxidative damage. This is because of its unique membrane structure and the presence of a very oxidation-sensitive phospholipid, cardiolipin. Cardiolipin is functionally required for the electron transport system. 

When mitochondrial cardiolipin and to a lesser degree other phosphatidyl phospholipids are damaged by oxidation, the chemical/electrical potential across the inner mitochondrial membrane is altered due to an increasingly “leaky” membrane that allows protons and ions to move across the membrane. This occurs because the oxidized membrane phospholipids no longer form a tight ionic/electrical “seal” or barrier.

Significant oxidative damage to mitochondrial membranes represents the point-of-no-return of programmed cell death pathways that culminate in apoptosis or regulated cell death leading to necrosis.  17

Repairing the Damaged Cell Membrane with Lipid Replacement Therapy®

The good news is that damaged lipids can be replaced.  In fact, a young healthy cell usually replaces damaged lipids in its membranes.  However, due to aging, eating a poor diet, exposure to environmental toxins, getting infections and certain illnesses, it becomes necessary to proactively replace the damaged lipids with new lipids. 

This can be done using Lipid Replacement Therapy (LRT®), which provides for the consumption of lipids that are the same as found in the cell membrane and organelle membranes. 

A product developed and manufactured by Nutritional Therapeutics Inc., called NTFactor®, is intended to reverse the damage done to our cells and mitochondria by oxidative stress through the process of Lipid Replacement Therapy®.

The NTFactor® formula is a unique combination that allows the healthy phospholipids to stay intact during transport through the body.

NT Factor Lipids® is based on U.S. Patent No. 8,877,239.  The lipid blend of NTFactor® includes:

  • Phosphatidic acid (PA)
  • Phosphatidyl-choline (PC)
  • Phosphatidyl-ethanolamine (PE)
  • Phosphatidyl-glycerol(PG) – (precursor for cardiolipin (CL))
  • Phosphatidyl-inositol (PI)
  • Phosphatidyl-serine (PS)
  • Digalactosyldiacylglyceride (DGDG)
  • Monoglactosyldiacylglyceride (MGDG)

NTFactor® uses a form of a stable oral supplement that emulates the amount and composition of the mitochondrial lipids assures that inappropriate oxidative membrane damage is prevented, damaged membrane phospholipids are replaced and mitochondrial membrane permeability is maintained in the optimal range.

Obtaining Phospholycolipids through Diet

Phospholycolipids can be obtained generally in the diet from meat, egg yolks, fish, turkey, chicken and beef.  Organ meats and egg yolks are among the best food sources of phosphoglycolipids, however, one would have to consume large portions of these foods at every meal to obtain the benefit of lipid replacement, which is unlikely and unhealthy.

The various lipids can be found in the following foods:

Phosphatidylcholine

Phosphatidylcholine can be obtained from egg yolk or soybeans.  Phosphatidylcholine is a major component of egg, soy and sunflower lecithin. 

Lecithin’s are mostly phospholipids, composed of phosphoric acid with choline, glycerol or other fatty acids usually glycolipids or triglyceride. Glycerophospholipids in lecithin include phosphatidylcholine, phosphatidylethanolamine, phosphatidylinositol, phosphatidylserine, and phosphatidic acid.

Phosphatidylethanolamine

Phosphatidylethanolamine is primarily found in lecithin.

Phosphatidylinositol

Phosphatidylinositol can be found in lecithin. 

Phosphatidylserine

Phosphatidylserine can be found in meat and fish. Only small amounts of phosphatidylserine can be found in dairy products or in vegetables, with the exception of white beans and soy lecithin.

Phosphatidylserine (PS) content in different foods

Food

PS Content in mg/100 g

Bovine brain

713

Atlantic mackerel

480

Chicken heart

414

Atlantic herring

360

Eel

335

Offal (average value)

305

Pig‘s spleen

239

Pig’s kidney

218

Tuna

194

Chicken leg, with skin, without bone

134

Chicken liver

123

White beans

107

Soft-shell clam

87

Chicken breast, with skin

85

Mullet

76

Veal

72

Beef

69

Pork

57

Pig’s liver

50

Turkey leg, without skin or bone

50

Turkey breast without skin

45

Crayfish

40

Cuttlefish

31

Atlantic cod

28

Anchovy

25

Whole grain barley

20

European hake

17

European pilchard (sardine)

16

Trout

14

Rice (unpolished)

3

Carrot

2

Ewe‘s Milk

2

Cow‘s Milk (whole, 3.5% fat)

1

Potato

1

 (Source:  Souci SW, Fachmann E, Kraut H (2008). Food Composition and Nutrition Tables. Medpharm Scientific Publishers Stuttgart)

Sphingomyelin

Sphingomyelin can be obtained from eggs or bovine brain.

Cholesterol

All animal-based foods contain cholesterol in varying amounts.  Cholesterol can be obtained from cheese, egg yolks, beef, pork, poultry, fish, and shrimp.  Cholesterol is not found in plant-based foods.   

#29 Garth Nicolson: How to Repair Mitochondria with Lipid Replacement

Natural Compounds That Promote Anti-Aggregation And Clearance of Amyloid Beta

Alzheimer’s disease is the most prevalent neurodegenerative disease in the growing population of elderly people. A hallmark of Alzheimer’s disease is the accumulation of plaques in the brain of Alzheimer’s disease patients. The plaques predominantly consist of aggregates of amyloid-beta generated in vivo by specific, proteolytic cleavage of the amyloid precursor protein. There is a growing body of evidence that amyloid-beta aggregates are ordered oligomers and the cause rather than a product of Alzheimer’s disease.

There are a number of studies that state that the accumulation of amyloid beta within the brain arises from an imbalance of the production and clearance of amyloid beta.  Most of the time in the case of Alzheimer’s disease, amyloid beta clearance is impaired.  1

The process of creating amyloid beta in the brain has multiple roles in the brain, including:  2

  • antioxidant activity
  • calcium homeostasis
  • metal ion sequestration
  • modulation of synaptic plasticity
  • neurogenesis
  • neurotrophic activity

This controlled homeostatic regulation allows for the normal functions of amyloid beta but also prevents accumulation of excess amyloid beta as a metabolic waste product. 

An imbalance in this homeostasis results in pathological and neurotoxic accumulations of cerebral amyloid beta.  3

Scientists have developed a number of therapeutic strategies as possible interventions against amyloid beta, two of which include:

  • Anti-aggregations agents
  • Clearance of amyloid beta

Anti-aggregations agents

Anti-aggregation prevent amyloid beta fragments from aggregating or clear aggregates once they are formed.  4

Clearance of amyloid beta

Impaired clearance of amyloid beta is now widely identified as a contributing factor towards Alzheimer’s disease progression.  5   In order to prevent pathological accumulations of amyloid beta in the brain, amyloid beta clearance from the cerebral milieu into periphery and out of the system is of prime importance. Improving amyloid beta clearance from the brain across the blood–brain barrier (BBB) and into blood plasma.

Clearance of amyloid beta is so important that recent evidence in humans suggests that impaired amyloid beta clearance is the main cause of pathological accumulations of cerebral amyloid beta in late onset Alzheimer’s disease and not the overproduction of amyloid beta.  6 

The purpose of this article is to examine and identify the natural compounds that act as either anti-aggregation agents or an agents for the clearance of amyloid beta, or both.  

Researchers have identified a number of natural compounds that have been effective as therapeutics for Alzheimer’s disease whether as an anti-aggregation agent and/or an agent for clearance of amyloid beta.  7 

These natural compounds include:

  • Baicalein
  • Curcumin
  • Ellagic acid
  • (−)-Epigallocatechin-3-gallate (EGCG)
  • Ferulic acid
  • Fisetin
  • Kaempferol
  • Luteolin
  • Malvidin
  • Melatonin
  • Myricetin
  • Nordihydroguaiaretic acid (NDGA)
  • Oleuropein Aglycone (OLE)
  • Proline Rich Polypeptide (Colostrinin™)
  • Quercetin
  • Resveratrol
  • Rosmarinic acid
  • Rutin
  • Vitamin A

Natural Compounds That Promote Anti-Aggregation And Clearance of Amyloid Beta

Natural CompoundAbstractReferences
BaicaleinOur data showed that baicalein inhibited the formation of α-syn oligomers in SH-SY5Y and Hela cells, and protected SH-SY5Y cells from α-syn-oligomer-induced toxicity. We also explored the effect of baicalein on amyloid-β peptide (Aβ) aggregation and toxicity. We found that baicalein can also inhibit Aβ fibrillation and oligomerisation, disaggregate pre-formed Aβ amyloid fibrils and prevent Aβ fibril-induced toxicity in PC12 cells. Our study indicates that baicalein is a good inhibitor of amyloid protein aggregation and toxicity. 1
CurcuminWhen fed to aged Tg2576 mice with advanced amyloid accumulation, curcumin labeled plaques and reduced amyloid levels and plaque burden. Hence, curcumin directly binds small beta-amyloid species to block aggregation and fibril formation in vitro and in vivo. These data suggest that low dose curcumin effectively disaggregates Abeta as well as prevents fibril and oligomer formation, supporting the rationale for curcumin use in clinical trials preventing or treating AD.2 2a
Ellagic acidHere, we tested the effects of ellagic acid (EA), a polyphenolic compound, on Abeta42 aggregation and neurotoxicity in vitro. EA promoted Abeta fibril formation and significant oligomer loss, contrary to previous results that polyphenols inhibited Abeta aggregation. 3
(−)-Epigallocatechin-3-gallate (EGCG)Here, we show that EGCG has the ability to convert large, mature α-synuclein and amyloid-β fibrils into smaller, amorphous protein aggregates that are nontoxic to mammalian cells. Mechanistic studies revealed that the compound directly binds to β-sheet-rich aggregates and mediates the conformational change without their disassembly into monomers or small diffusible oligomers. These findings suggest that EGCG is a potent remodeling agent of mature amyloid fibrils.4
The polyphenol (-)-epigallocatechin gallate efficiently inhibits the fibrillogenesis of both alpha-synuclein and amyloid-beta by directly binding to the natively unfolded polypeptides and preventing their conversion into toxic, on-pathway aggregation intermediates. Instead of beta-sheet-rich amyloid, the formation of unstructured, nontoxic alpha-synuclein and amyloid-beta oligomers of a new type is promoted, suggesting a generic effect on aggregation pathways in neurodegenerative diseases.5
Ferulic acidFerulic acid dose-dependently inhibited fAbeta formation from amyloid beta-peptide, as well as their extension. Moreover, it destabilized preformed fAbetas. The overall activity of the molecules examined was in the order of: Cur > FA > rifampicin = tetracycline. FA could be a key molecule for the development of therapeutics for AD.6
Chronic (for 6 months from the age of 6 to 12 months) oral administration of ferulic acid at a dose of 5.3 mg/kg/day significantly enhanced the performance in novel-object recognition task, and reduced amyloid deposition and interleukin-1 beta (IL-1β) levels in the frontal cortex. These results suggest that ferulic acid at a certain dosage could be useful for prevention and treatment of AD.7
FisetinFisetin (3,3',4',7-tetrahydroxyflavone) has been found to be neuroprotective, induce neuronal differentiation, enhance memory, and inhibit the aggregation of the amyloid beta protein (Abeta) that may cause the progressive neuronal loss in Alzheimer's disease. 8
The natural flavonoid fisetin (3,3',4',7-tetrahydroxyflavone) is neurotrophic and prevents fibril formation of amyloid β protein (Aβ). It is a promising lead compound for the development of therapeutic drugs for Alzheimer's disease.  9
KaempferolKaempferol was shown to have protective effects against oxidative stress-induced cytotoxicity in PC12 cells. Administration of kaempferol also significantly reversed amyloid beta peptide (Abeta)-induced impaired performance in a Y-maze test.10
Luteolin These results indicated that luteolin from the Elsholtzia rugulosa exerted neroprotective effects through mechanisms that decrease AβPP expression, lower Aβ secretion, regulate the redox imbalance, preserve mitochondrial function, and depress the caspase family-related apoptosis.11
MalvidinWe have identified four novel polyphenols which could be efficient fibril inhibitors in Alzheimer's disease: malvidin and its glucoside and curculigosides B and D. We suggest that molecules with the particular C(6)-linkers-C(6) structure could be potent inhibitors. From the results reported for the flavan-3-ol family, their anti-amyloidogenic effects against whole peptides (1-40 and 1-42) could involve several binding sites.12
MelatoninWe report that melatonin, a hormone recently found to protect neurons against Abeta toxicity, interacts with Abeta1-40 and Abeta1-42 and inhibits the progressive formation of beta-sheets and amyloid fibrils. In sharp contrast with conventional anti-oxidants and available anti-amyloidogenic compounds, melatonin crosses the blood-brain barrier, is relatively devoid of toxicity, and constitutes a potential new therapeutic agent in Alzheimer's disease.13
Inhibition of beta-sheets and fibrils could not be accomplished in control experiments when a free radical scavenger or a melatonin analog were substituted for melatonin under otherwise identical conditions. In sharp contrast with conventional anti-oxidants and available anti-amyloidogenic compounds, melatonin crosses the blood-brain barrier, is relatively devoid of toxicity, and constitutes a potential new therapeutic agent in Alzheimer's disease.14
MyricetinMyricetin was the most potent compound myricetin to the neurotoxic oligomers rather than monomers. These findings suggest that flavonoids, especially Myricetin, exert an anti-amyloidogenic effect in vitro by preferentially and reversibly binding to the amyloid fibril structure of fAbeta, rather than to Abeta monomers.15
Nordihydroguaiaretic acid (NDGA)In cell culture experiments, fAbeta disrupted by NDGA were less toxic than intact fAbeta, as demonstrated by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay. Although the mechanisms by which NDGA inhibits fAbeta formation from Abeta, as well as breaking down pre-formed fAbetain vitro, are still unclear, NDGA could be a key molecule for the development of therapeutics for AD.16
Oleuropein Aglycone (OLE)Here we report that oleuropein aglycon also hinders amyloid aggregation of Aβ(1-42) and its cytotoxicity, suggesting a general effect of such polyphenol. We also show that oleuropein aglycon is maximally effective when is present at the beginning of the aggregation process; furthermore, when added to preformed fibrils, it does not induce the release of toxic oligomers but, rather, neutralizes any residual toxicity possibly arising from the residual presence of traces of soluble oligomers and other toxic aggregates. The possible use of this polyphenol as anti-aggregation molecule is discussed in the light of these data.17
Proline Rich Polypeptide (Colostrinin™)Colostrinin™ is a mixture of proline-rich polypeptides (PRP) from ovine (sheep) colostrums. Colostrinin inhibits amyloid beta aggregation and facilitates disassembly of existing aggregates by disrupting beta-sheets bonding.18
QuercetinQuercetin is an effective amyloid aggregation inhibitor and inhibits amyloid beta fibrillization, but not its toxic oligomerization19
ResveratrolHere we show that resveratrol (trans-3,4',5-trihydroxystilbene), a naturally occurring polyphenol mainly found in grapes and red wine, markedly lowers the levels of secreted and intracellular amyloid-beta (Abeta) peptides produced from different cell lines. Resveratrol does not inhibit Abeta production, because it has no effect on the Abeta-producing enzymes beta- and gamma-secretases, but promotes instead intracellular degradation of Abeta via a mechanism that involves the proteasome. 20
In conjunction with the concept that Abeta oligomers are linked to Abeta toxicity, we speculate that aside from potential antioxidant activities, resveratrol may directly bind to Abeta42, interfere in Abeta42 aggregation, change the Abeta42 oligomer conformation and attenuate Abeta42 oligomeric cytotoxicity. 21
Rosmarinic acidRosmarinic acid had especially strong anti-amylid beta aggregation effects in vitro22
Rosmarinic acid reduced a number of events induced by Abeta. These include reactive oxygen species formation, lipid peroxidation, DNA fragmentation, caspase-3 activation, and tau protein hyperphosphorylation. Moreover, rosmarinic acid inhibited phosphorylated p38 mitogen-activated protein kinase but not glycogen synthase kinase 3beta activation. These data show the neuroprotective effect of sage against Abeta-induced toxicity, which could validate the traditional use of this spice in the treatment of AD. Rosmarinic acid could contribute, at least in part, for sage-induced neuroprotective effect.23
RutinHere, we show that the common dietary flavonoid, rutin, can dose-dependently inhibit Aβ42 fibrillization and attenuate Aβ42-induced cytotoxicity in SH-SY5Y neuroblastoma cells. 24
Vitamin A (beta-carotene)In this study, we used fluorescence spectroscopy with thioflavin T (ThT) and electron microscopy to examine the effects of vitamin A (retinol, retinal, and retinoic acid), beta-carotene, and vitamins B2, B6, C, and E on the formation, extension, and destabilization of beta-amyloid fibrils (fAbeta) in vitro. Among them, vitamin A and beta-carotene dose-dependently inhibited formation of fAbeta from fresh Abeta, as well as their extension. Moreover, they dose-dependently destabilized preformed fAbetas.25
Withanolides (Withania somnifera)The researchers found that using Withania somnifera extracts, comprising 75% withanolides and 20% withanosides, reversed plaque pathology and reduced the amyloid beta burden in middle-aged and old APP/PS1 mice through up-regulation of liver LRPI, leading to increased clearance of amyloid beta.26

Cover Photo:  Rosemary plant and flower

Can a Spoonful of Ceylon Cinnamon Make the Parkinson’s Go Down?

Parkinson’s disease is a degenerative disorder of the central nervous system in which dopamine generating cells in the substantia nigra die.  This then affects the motor system with regards to movement related activities, such as, shaking, rigidity, difficulty in walking and slowness in walking.

Two proteins in the brain act to protect neurons in the substantia nigra from cell death.  The first is Protein deglycase DJ-1 (DJ-1) which protects neurons against oxidative stress and cell death   The second is Parkin which helps degrade one or more proteins toxic to dopaminergic neurons.  The loss of function of the Parkin protein leads to dopaminergic cell death, which then can lead to Parkinson’s disease. Parkin and DJ-1 are known to stimulate and support the survival of existing dopaminergic neurons. It has been identified that Parkin and Protein deglycase DJ-1 decrease in the brain of Parkinson’s patients.  1

An interesting article published in the Journal of Neuroimmune Pharmacology in September 2014 entitled Cinnamon Treatment Upregulates Neuroprotective Proteins Parkin and DJ-1 and Protects Dopaminergic Neurons in a Mouse Model of Parkinson’s Disease explored a novel use of cinnamon in upregulating Parkin and DJ-1 and protecting dopaminergic neurons in a MPTP mouse model of Parkinson’s.

The authors from Rush University Medical Center’s Department of Neurological Sciences, Kalipada Pahan and Saurabh Khasnavis found that after oral feeding, ground cinnamon (Ceylon cinnamon (Cinnamonum verum)) is metabolized into sodium benzoate, which then enters into the brain, which then:  2

  • Stops the loss of Parkin and Protein deglycase DJ-1
  • Protects neurons
  • Normalizes neurotransmitter levels
  • Improves motor functions in mice with Parkinson’s

The authors also found that the oral treatment of MPTP-intoxicated mice with cinnamon powder and sodium benzoate:  3

  • Reduces the nigral expression of iNOS
  • Blocks nigral loss of Parkin and DJ-1
  • Protects the nigrostriatal axis
  • Restores locomotor activities

They suggested that cinnamon may be used to protect dopaminergic neurons in the nigra of Parkinson’s patients.

The authors of the study used True Cinnamon or Ceylon cinnamon (Cinnamonum verum) rather than using Chinese cinnamon (Cinnamomum cassia).  They stated that “Although both types of cinnamon are metabolized into sodium benzoate, by mass spectrometric analysis, we have seen that Ceylon cinnamon is much more pure than Chinese cinnamon as the latter contains coumarin, a hepatotoxic molecule.”  4

The use of Ceylon cinnamon could potentially be one of the safest approaches to halt disease progression in Parkinson’s patients.”  5

Ceylon cinnamon contains a major compound named cinnamaldehyde, which is converted into cinnamic acid by oxidation. In the liver, this cinnamic acid is β-oxidized to benzoate that exists as sodium salt (NaB) or benzoyl-CoA.   6

The authors concluded their study by stating, “Now we need to translate this finding to the clinic and test ground cinnamon in patients with PD. If these results are replicated in PD patients, it would be a remarkable advance in the treatment of this devastating neurodegenerative disease.”  7


It is important to note that if one is to consume a teaspoon or less of Ceylon cinnamon or True cinnamon (Cinnamonum verum) daily, it should be consumed in liquid or in food, and never in its dry form directly in the mouth as this could cause choking

Also make sure that you consume Ceylon cinnamon or True cinnamon (Cinnamonum verum or Cinnamomum Zeylanicum) and not Chinese cinnamon (Cinnamomum cassia or Cinnamomum Aromaticum) or Indonesian cinammon (Cinnamomum Burmanni) or Saigon cinammon (Cinnamomum Loureiroi), as these three cassia cinnamons can be hepatotoxic (damaging to the liver) in large quantities and on a frequent basis.

A common method of consuming Ceylon cinnamon or True cinnamon (Cinnamonum verum or Cinnamomum Zeylanicum) is to mix it in a smoothie with vegetables/fruit and protein powder.


Resources:

Cinnamon Vogue – CEYLON CINNAMON POWDER USDA ORGANIC

Ceylon cinnamon or True cinnamon (Cinnamonum verum)

Modulating the Genetic Factors (ApoE) of Alzheimer’s Disease With Positive Behaviors and Natural Substances

Causitive Factors of Dementia and Alzheimer’s Disease

It is generally believed that the onset of dementia and Alzheimer’s disease is the consequences of complex interactions among:  1

  • genetic factors
  • environmental factors
  • lifestyle factors

The main features of dementia and Alzheimer’s disease are the presence of:

  • extracellular amyloid beta protein plaques
  • intracellular neurofibrillary tangles of tau proteins (NFTs)
  • loss of neurons and synapses in the cerebral cortex and certain subcortical regions in the brain

Image result for amyloid beta plaques

Figure 1.  Amyloid beta protein plaques and intracellular neurofibrillary tangles of tau proteins  (Source)

Image result for loss of neurons and synapses in the cerebral cortex

Figure 2.  Loss of neurons and synapses in the cerebral cortex  (Source)

This article focuses on the genetic factors as a potential cause for the late-onset of Alzheimer’s disease and what actions can be taken to modulate these genetic factors as it related to the most important genetic factor known as apolipoprotein E (ApoE).

Genetic Factors

Studies have demonstrated that Alzheimer’s disease is related to polymorphisms of at least four (4) genes:

  • amyloid precursor protein (APP)
  • presenilin (PS-1)
  • presenilin (PS-2)
  • apolipoprotein E (ApoE)

Polymorphisms in the three genes, amyloid protein precursor (APP), presenilin (PS)-1 and PS-2, is estimated to be the cause of early-onset (which is less than 60 years of age) autosomal dominant Alzheimer’s disease, which accounts for less than 1% of Alzheimer’s disease cases.  2

There are multiple genetic, environmental and lifestyle factors involved in late-onset Alzheimer’s disease, yet impairment in amyloid-beta clearance by ApoE is a major contributor to development of the disease.

Apolipoprotein E (ApoE)

Apolipoprotein E (ApoE) is a class of apolipoprotein found in the chylomicron and Intermediate-density lipoprotein (IDLs) that is essential for the normal catabolism of triglyceride-rich lipoprotein constituents. 

ApoE is mainly produced by astrocytes, and transports cholesterol to neurons via ApoE receptors, which are members of the low density lipoprotein receptor gene family.  ApoE is the principal cholesterol carrier in the brain and encodes for a protein that transports cholesterol, fats and fat-soluble vitamins through the blood.  

ApoE also contributes to the maintenance and repair of nerve cells.

PBB Protein APOE.jpg

Figure 3.  Apolipoprotein E (ApoE)  (Source)

There are three (3) major polymorphisms or alleles in the ApoE gene:

  • ApoE-ε2  (good one)
  • ApoE-ε3  (neutral)
  • ApoE-ε4  (problematic)

Since we carry two copies of the APOE gene, one from our mother and one from our father, the combination of alleles determines our ApoE3 genotype, for which there are six possible genotypes:

  • E2/E2
  • E3/E3
  • E4/E4
  • E2/E3
  • E2/E4
  • E3/E4

The ApoE-ε2 polymorphism, the most desirable to have, is associated with lower cholesterol levels and it actually may protect against Alzheimer’s disease in some populations and may decrease the risk.  3  

The ApoE-ε3 allele has a frequency of approximately 79 percent and is considered the “neutral” Apo E genotype. This means that for 79% of the population, a genetic polymorphism of this gene does not cause dementia or heart disease.  

The E2 allele is the one that is the most efficient in clearing and removing the amyloid-beta plaques from the brain.  The second most efficient allele is the E3 version, which does an average job of removing amyloid-beta plaques.

The E4 allele is the least efficient version in removing and clearing amyloid-beta plaques from the brain.  This results in more plaques building up and creating a much greater risk of developing Alzheimer’s disease.

The best genotype to have is E2/E2.

The worst genotype to have is E4/E4.

There are certain percentages of the population that carry certain genotypes:

  • Around 55% of the population have the E3/E3 genotype, which is the most common, equating to average risk  
  • Around 25% of the population have the E3/E4 genotype
  • Around 15% of the population have the E2/E3 genotype

ApoE-ε4 Allele

ApoE-ε4 is a major genetic risk factor for late-onset Alzheimer’s disease.  

Individuals carrying the E4 allele are at an increased risk of Alzheimer’s disease.  Having one allele of ApoE4 increases the risk of Alzheimer’s disease, and if two ApoE4 alleles are present, the risk is even higher.  15

However, many individuals with the ApoE-ε4 allele never develop the disease and many patients with Alzheimer’s disease do not have the ApoE-ε4 allele.  

With an allele frequency of approximately 14%, the ApoE-ε4 polymorphism has been implicated in the following diseases:

  • atherosclerosis  4
  • Alzheimer’s disease  5
  • impaired cognitive function  6
  • reduced hippocampal volume  7 
  • HIV  8 
  • faster disease progression in multiple sclerosis  9
  • unfavorable outcome after traumatic brain injury  10 
  • ischemic cerebrovascular disease  11 
  • sleep apnea  12
  • accelerated telomere shortening  13
  • reduced neurite outgrowth  14  

Image result for Apolipoprotein E

Figure 4.  Apolipoprotein E and Alzheimer disease  (Source)

Those patients with two ε4 alleles of the APOE gene have up to 20 times the risk of developing Alzheimer’s disease.  16  The lifetime risk estimate of developing Alzheimer’s disease for individuals with one copy of the apoE4 allele (approximately 25% of the population) is approximately 30%. 17

According to the National Institute of Health, inheriting a single copy of ApoE4 from a parent increases the risk of Alzheimer’s disease by about three-fold. Inheriting two copies, one from each parent, increases the risk by about 12-fold.

ApoE generally is an anti-inflammatory and is able to break down the amyloid beta proteins that are a cause of Alzheimer’s disease.  The ApoE-ε4 allele is limited in its ability to function as an anti-inflammatory and to break down amyloid beta proteins. 18

Increasing the Production and Function of ApoE-ε4

If a person has one E4 allele or two E4 alleles (E4/E4, which is the worst and carries the highest risk for Alzheimer’s disease), then they can and should take proactive and aggressive preventive action to increase the production and function of the ApoE-ε4 allele.

You ultimately want your ApoE working effeciently to help control and remove the harmful buildup of amyloid-beta plaques.

Since the ApoE-ε4 allele does not function as efficiently as the ApoE-ε2, there are certain behaviors that can be done and substances that can be taken to increase its production and function. 

Behavioral Actions

There are certain behavioral actions that can be taken to increase to production and function of the ApoE, such as:

  • Eat a Ketogenic diet  19
  • APOE Stabilization by Exercise  20
  • Reduce elevated total cholesterol level and blood pressure 21
  • Learning and education (allowing the brain to constantly learn new and interesting in-depth subjects)  
  • 22

Natural Substances that Increase the Production and Function of ApoE-ε4

There are also natural substances that be consumed that have shown to increase the production and function of ApoE, especially in the case of a low functioning E4 single of double allele.  

These substances are listed in the Table below:

Increasing the Production and Function of ApoE-ε4

CategorySubstanceReference
Fatty Acids
DHA Ref.
Butyrate Ref.
Polyphenols
Curcumin Ref.   Ref.
Vitamins
Vitamin A (Retinol)   Ref.
Citicoline (cytidine diphosphate-choline (CDP-Choline) Ref.

Resources:

In order to see what your genotype in the ApoE gene, especially if your have the ApoE-ε4 polymorphism, you need to order a DNA and Genetic Test.  There are a number of testing companies.  The most popular are:

23andMe

Ancestry

Genos

Once you have ordered and received your DNA and Genetic Test from the testing company, you can then download your data to one of a number of websites that will analyze your genetic data and provide information on the polymorphisms of the ApoE gene and your specific genotype. 

A number of companies will analyze your genetic data and include:

SelfDecode

Livewello

Infinome

Promethease

Codegen.eu

All of the 5 companies above will receive the 23andMe genetic data.

Another way to test for your genotype and the ApoE-ε4 polymorphism can be done by ordering the following test from Life Extension:

Life Extension – ApoE Genetic Test for Alzheimer’s and Cardiac Risk

Sample Report (PDF)

Videos:

Dr. Ben Lynch – Alzheimer’s Dirty Gene APOE4

AHS16 – Steven Gundry – Dietary Management of the Apo E 4

NutritionFacts.org – The Alzheimer’s Gene: Controlling ApoE

Apo E Gene’s connection with Alzheimer’s Disease, Heart Disease and more

Do you have Apo E 4 Dementia risk, Heart Attack diet risk; Apo(e) 4 and alcohol