Inhibiting the Fibrillogenesis of Alpha-synuclein and Amyloid-beta by Natural Substances

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Synucleinopathies

A group of neurodegenerative disorders characterized by fibrillary aggregates of alpha-synuclein protein in the cytoplasm of selective populations of neurons and glia is called Synucleinopathies or alpha-Synucleinopathies. 

Synucleinopathies include:

  • Parkinson’s disease (PD)
  • Dementia with Lewy bodies (DLB)
  • Pure autonomic failure (PAF)
  • Multiple system atrophy (MSA)

These neurological disorders are characterized by a chronic and progressive decline in the following bodily functions:

  • autonomic
  • behavioral
  • cognitive
  • motor skills

Alpha-synuclein protein

Synucleinopathies are caused by the abnormal accumulation of aggregates of alpha-synuclein protein in:

  • glial cells
  • nerve fibers
  • neurons

Alpha-synuclein is a protein that is abundant in the human brain and is predominantly expressed in the:

  • cerebellum
  • hippocampus
  • neocortex
  • substantia nigra
  • thalamus

It is also found in smaller amounts in the heart, muscles, and other tissues. 

Figure 1.  This a rendering of the Alpha-synuclein protein, based the PDB file of 1XQ8 using Rasmol.  (Source:  Hantanplan)

In the brain, alpha-synuclein is found primarily at the end of the neurons in specialized structures called the presynaptic terminal. The presynaptic terminal is a specialized area within the axon of the presynaptic cell that contains neurotransmitters enclosed in small membrane-bound spheres called synaptic vesicles.  The release of neurotransmitters from the presynaptic terminal relays signals between neurons.  Dysfunctional presynaptic terminals due to aggregation of alpha-synuclein can compromise normal brain function.

Lewy bodies

When alpha-synuclein aggregates, it forms insoluble fibrils in pathological conditions characterized by Lewy bodies.  Alpha-synuclein is the primary structural component of Lewy body fibrils, even though Lewy bodies may also contain:

  • alpha B crystallin
  • neurofilament protein
  • tau protein
  • ubiquitin

Lewy neurites are abnormal neurites in diseased neurons, containing granular material and abnormal alpha-synuclein filaments similar to those found in Lewy bodies.

Figure 2.  Microscope photograph of a Lewy body  (Source:  By Dr. Andreas Becker upload here Penarc – Own work, CC BY-SA 3.0)

Inhibiting the Fibrillogenesis of alpha-synuclein and amyloid-beta by Natural Substances

Researchers have focused on finding ways to inhibit the fibrillogenesis of alpha-synuclein in order to halt the formation of pathological conditions characterized by Lewy bodies.

Beginning in 2008, then in 2010 and 2011, researchers have been able to identify two natural substances that not only inhibits the fibrillogenesis of alpha-synuclein, but also at the same time inhibits amyloid-beta fibrillogenesis, the major cause of vascular dementia and Alzheimer’s disease.

These two natural substances include:

  • (-)-epigallocatechin gallate  (EGCG)  
  • theaflavins  

(-)-epigallocatechin gallate (EGCG) is found in high content in the dried leaves of white tea (4245 mg per 100 g), green tea (7380 mg per 100 g) and, in smaller quantities, black tea.  Smaller trace amounts can be found in apple skin, plums, onions, hazelnuts, and pecans.

Theaflavins are formed from the condensation of flavan-3-ols in tea leaves during the enzymatic oxidation of black tea.

In 2008, researchers demonstrated the redirection of amyloid fibril formation through the action of a small molecule, resulting in off-pathway, highly stable oligomers.

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.  1

Researchers in 2010 reconfirmed the fact that the polyphenol (-)-epi-gallocatechine gallate (EGCG) inhibits alpha-synuclein and amyloid-beta fibrillogenesis.  2  They showed that EGCG has the ability to convert large, mature alpha-synuclein and amyloid-beta fibrils into smaller, amorphous protein aggregates that are nontoxic to mammalian cells.

Finally, in 2011, researchers showed that theaflavins (TF1, TF2a, TF2b, and TF3), the main polyphenolic components found in fermented black tea, are potent inhibitors of amyloid-beta and alpha-synuclein fibrillogenesis.  3  Theaflavins stimulate the assembly of amyloid-beta and alpha-synuclein into nontoxic, spherical aggregates that are incompetent in seeding amyloid formation and remodel amyloid-beta fibrils into nontoxic aggregates.

Their conclusion suggested that theaflavins might be used to remove toxic amyloid deposits.

These three studies confirm the fact that adding green tea, white tea and/or black tea to your diet in order to obtain both EGCG and theaflavins may be a promising therapy to prevent Synucleinopathies, Dementia and Alzheimer’s disease.   

Cover photo credit: SUNY Oneonta