Biomedical Science and Research Journals | Natural Products for the Therapy of Proteinopathies Underlying the Neurodegenerative Conditions: Protein Misfolding and Fibrillization in Alzheimer’s Disease and Parkinson’s Disease
Natural Products for the Therapy of Proteinopathies Underlying the Neurodegenerative Conditions: Protein Misfolding and Fibrillization in Alzheimer’s Disease and Parkinson’s Disease
Introduction
Significant progress has been made in our understanding of
dysregulated proteostasis and protein misfolding which underlie
the pathogenesis of such neurodegenerative diseases as Alzheimer’s
disease (AD) and Parkinson’s disease (PD). In the 1990s the
kinetics of β-amyloid (Aβ) fibrillization was well characterized
[1,2]. Epidemiology had shown that mutations in amyloid precursor
protein (APP) or the beta- and gamma-secretases which elevate
the level of Aβ in the brain, as well as mutations which increase
the propensity for Aβ to polymerize, are strongly associated with
the development of Alzheimer’s disease. Oligomers of Aβ are more
neurotoxic than the monomers [3-5]. These observations suggested
that molecules which would interfere with polymerization and
fibrillization might slow the progression of AD. During the testing of
natural compounds, Thioflavin-T (Th-T) was often used to monitor
the state of Aβ polymerization [6].
The tendency for many proteins and peptides to convert from
their native functional state into intractable amyloid aggregates
was found to underlie multiple human disorders including
Alzheimer and Parkinson diseases, type II diabetes, prion disease
and several systemic amyloidosis (e.g. Aβ, αs, PrP, τ, IAPP, TDP-43,
p53) [7-15]. Multiple therapeutic strategies have been employed
to find disease-modifying agents against amyloidosis [16]. Some
natural compounds found in the diet have anti-amyloid effects and
may reduce the risk for AD and T2D [17,18]. Epidemiologic studies
have suggested that diets with a high intake of flavonoids and
polyphenolic compounds may have protective effects against AD,
T2D and dementia [19-21]. Several polyphenols have progressed
to clinical trials for the treatment of AD including resveratrol,
curcumin, epigallocatechin-3-gallate (EGCG) and palm fruit
bioactive [19,22,23].
Abbreviations: Aβ: Beta-Amyloid; αs: Alpha-Synuclein; τ: Tau
Protein; PRP: Prion Protein; IAPP: Islet Amyloid Peptide; TDP-43:
TAR DNA-Binding Protein 43; P53: Tumour Suppressor P53; T2D:
Type 2 Diabetes Mellitus; AD: Alzheimer’s Disease; PD: Parkinson’s
Disease; ALS: Amyotrophic Lateral Sclerosis
These polyphenols, demonstrating a range of anti-inflammatory,
antioxidant and metal chelating bioactivities, have served as
structural backbones in the computational design of novel drugs
[24,25]. A PubMed literature review of natural compounds which
modulate amyloid aggregation revealed 72 compounds, of which 44
are phenolic compounds including 16 flavonoids, 4 anthraquinones,
13 alkaloids (including 3 pyridines, 3 indoles, 2 porphyrins),
steroids and terpenes [26].
Epidemiologic studies of diets have shown that the regular
ingestion of curcumin, myricetin, EGCG, along with green tea
polyphenols is associated with healthy cognitive function [19,27,28].
Cohort studies on the moderate consumption of red wine suggest
that resveratrol reduces the risk of dementia, AD or cognitive
decline associated with aging [21,29]
Among the 72 anti-amyloid
compounds identified in the PubMed search are many phenolic
compounds which are found in brain-healthy diets associated with
reduced risk of aging-associated amyloid pathologies [19,30,31].
These compounds include: EGCG and myricetin found in green
tea; curcumin found in turmeric; caffeic acid and rosmarinic acid
found in culinary herbs; oleuropein and oleocanthal found in olive oil;
resveratrol found in red wine and grapes; genistein found in
legumes; and cinnamaldehyde found in cinnamon. Investigations
into the mechanism of action by which these compounds inhibit
amyloid aggregation show that some exert their effects through the
formation of covalent bonds [32-39] and others exert their effects
through non-covalent interactions [40-57].
The proteinopathies, involving protein misfolding and
aggregation into toxic fibrillar deposits, are common to multiple
neurodegenerative conditions including AD, PD, ALS, TDP-43,
IAPP, prion diseases as well as to such systemic disorders of T2D
and systemic amyloidosis [58-62]. Clinical trials aimed at reducing
the level of toxic misfolded protein aggregates have not been
successful over the past decade, perhaps due to a futile intervention
following irreversible and irreparable cell and tissue damage. More
promising is the potential for preventing the organ damage in the
first place, through the regular intake of a diet rich in phenolics,
which have dual activity as both amyloid aggregation inhibitors and
as antioxidants.
Beta amyloid (Aβ) and tau (τ) aggregates are pathognomonic
for AD [63]; alpha-synuclein (αs) deposits are seen in PD [64]; prion
diseases and transmissible spongiform encephalopathies (TSE)
present with misfolded prion protein (PrPSC) [65]; aggregates of
superoxide dismutase 1 (SOD-1) and TAR DNA-binding protein 43
(TDP-43) characterize ALS [66-68]; and fronto-temporal dementia
(FTD) also manifests aggregates of TDP-43 [69]; Huntington’s
disease manifests aggregation of glutamine-rich (polyQ) Huntingtin
protein (htt) [70]. The toxic protein aggregates dysregulate the
cellular metabolism and activate a complex cascade of events
which may lead to acute inflammation or apoptosis. The amyloid
aggregates may also block proteasomal activities and cause a
marked disturbance in proteostasis. Beta-sheet-rich proteins jam
the entry site to the catalytic core, thereby blocking the proteasome
system [71-73]. Often the autophagy system seems impaired in
these diseases with accumulation of autophagic vacuoles [74,76].
The toxic aggregates also disrupt permeability of cell membranes,
impair mitochondrial function, increase reactive oxygen species,
induce acute inflammation and disrupt proteostasis. The protein
aggregates also expose hydrophobic portions which interact
abnormally with other cellular proteins, which results in their
sequestration and loss of normal function [61,77,78].
Epigallocatechin-3-gallate (EGCG) is a flavanol found in
green tea leaves [79] EGCG has demonstrated neuroprotective,
antioxidant, antibacterial and antitumor activity in vitro and in
vivo [80,81] EGCG reduces the aggregation and toxicity of a wide
range of proteins involved in proteinopathies. Some papers report
that EGCG acts at an early stage of aggregation by binding with the
proteins in a non-sequence specific manner [82]. Evidence suggests
that it may bind to and stabilize unfolded conformations of Aβ
and αs, thereby reducing fibrillation and re-directing the proteins
from the aggregation cascade to off-pathway amorphous non-toxic
aggregates.45 EGCG also binds to partially misfolded tau [83].
Through its multiple mechanisms of action on inhibiting amyloid
aggregation suggests its potential use in preventive clinical trials
on AD.
Curcumin is a biphenolic compound found in Curcuma longa,
the Indian spice turmeric used in curry dishes, has strongly
documented anti-inflammatory and antioxidant properties [84,85].
Based on its general activity inhibiting amyloid aggregation,
Curcumin has shown beneficial effects in AD, PD, T2D and prion
diseases [84,86,87] Clinical trials are underway for Curcumin for AD
and T2D. Curcumin directly binds to Aβ and inhibits its aggregation
in vitro [88] and in vivo [89]. Curcumin also disaggregates peptides
from toxic aggregates.
Resveratrol is a natural phytoalexin stilbenoid polyphenolic
compound found in grapes, berries, soybeans, peanuts and red
wine. Resveratrol inhibits the aggregation of Aβ through selective
transformation of the oligomers and shuttling them into off-pathway
species which are unable to aggregate [90]. Resveratrol can bind
multiple conformations of Aβ including Aβ42, Aβ40 and fibrillar Aβ
[91]. Resveratrol is able to disaggregate Aβ from Aβ42 fibrils [92]
In cell culture, resveratrol reduces the hyperphosphorylation of
tau proteins [93]. In transgenic AD murine models, resveratrol has
been shown to reduce amyloid plaque deposition without directly
affecting the processing of APP [94,95].
In the transgenic murine AD models, resveratrol also:
1. Improves cognitive function [96,97],
2. Protects permeability of the blood-brain barrier [98],
3. Reduces acute inflammatory response through a decrease
in microgliosis, and
Botes and Sinskey have observed that Palm Fruit Bioactive,
comprising a polyphenol-rich extract from the Elaeis guineensis,
reduce the cytotoxicity of aggregated α-synuclein in a transgenic
yeast rescue assay [101]. Other promising natural agents with
potent anti-amyloid aggregation properties include: Apigenin,
Fisetin, Kaempferol, Morin, Quercetin, Myricetin, Brazilin, Gallic
acid, Oleocanthal, oleuropein, oleuropein aglycone, Orcein,
Rosmarinic acid, Tanshinones, and Tannic acid. These natural
compounds have been undergoing extensive investigation for their
potential in preventing or reducing the proteinopathies, but a more
detailed discussion of them is beyond the scope of this mini review.
Conclusion
The clinical trials with these natural compounds over the
past decade have been disappointing but this may be the result of
attempting to overcome irreversible and irreparable damage to the
brain. We must consider implementing a diet rich in these natural
anti-amyloid compounds early in life to prevent the neurotoxicity
of these amyloid aggregates and thus prevent the inception and
progression of these devastating neurodegenerative conditions.
The answer may be in the prevention rather than the cure of these
conditions.
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