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- Resveratrol
- Autophagy
- Alzheimer's Disease
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Date:
05-15-2018 | HC# 101754-592
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Re: Autophagy-stimulating Activities of Resveratrol Might Contribute to Mitigation of Alzheimer's Disease
Kou
X, Chen N. Resveratrol as a natural autophagy regulator for prevention and
treatment of Alzheimer's disease. Nutrients.
2017;9(9):927. doi: 10.3390/nu9090927.
Resveratrol
is a polyphenol best known for its occurrence in grape (Vitis vinifera, Vitaceae) skin and seeds. Research shows that it
may be useful to prevent and treat degenerative brain disorders such as Alzheimer's
disease (AD). The purpose of this report is to review the molecular mechanisms
of resveratrol in regulating autophagy and microRNAs (miRNAs) during AD. The
report begins with an extensive review of the molecular mechanisms of AD as
currently understood to enhance readers' understanding of how resveratrol may play
a role in preventing/treating AD.
Autophagy in AD
The
primary pathological markers of AD are accumulations of misfolded proteins,
including amyloid-β (Aβ) plaques and neurofibrillary tangles formed of highly
phosphorylated Tau protein, in the brain.
The
autophagy-lysosome system digests long-lived and abnormal protein complexes and
organelles. Hence, autophagy is needed for healthy neural function; however, it
decreases in aging. Declining autophagy leads to increased reactive oxygen
species (ROS), cell death, and neurodegeneration. Abnormal accumulation of autophagic vacuoles is apparent in neurons in
some neurodegenerative diseases and in a mouse model of AD. The level of
autophagy-related Beclin1 is significantly reduced in brain tissue of patients
with AD. In a mouse model of AD, lower Beclin1 levels lead to Aβ accumulation and neurodegeneration. Autophagy is
regulated by multiple signal pathways; for example, the mammalian target of rapamycin
(mTOR) pathway negatively regulates autophagy, so substances inhibiting mTOR
can increase autophagy in neurons. Upregulating autophagy may provide a
protective effect and is a target for AD treatment.
MicroRNAs in AD
miRNAs
are small, non-coding RNAs that can reduce messenger RNA (mRNA) stability and
protein expression by targeting specific mRNAs. They are involved in
neurodevelopment and synaptic plasticity. miRNAs also have a role in the
production of pro-inflammatory cytokines in AD, while reduced production of
some miRNAs can increase the production of Aβ. Aβ peptide aggregation results
from imbalanced Aβ production and disordered Aβ clearance. It may be involved
in the development and progression of AD. [Note: It remains controversial
whether Aβ plaque accumulation is a cause or a consequence of AD.] There is
also some limited evidence that decline in miRNAs may increase production of
phosphorylated Tau protein. Autophagy-related miRNAs are thought to be involved
in the early stage of AD, while others may be involved in the late stage of AD
and other degenerative diseases.
Resveratrol and AD
In
vitro, resveratrol can reduce Aβ-induced cytotoxicity and cell apoptosis.
Several in vivo studies suggest that resveratrol may be beneficial in
preventing/treating AD. In a mouse model of AD, resveratrol treatment prevented
neurodegeneration and cognitive decline. In a rat model of AD, resveratrol
improved memory, putatively by increasing antioxidant activity. In amyloid
precursor protein (APP)-transgenic mice, resveratrol decreased Aβ levels and
brain amyloid deposition. In humans, consumption of red wine, rich in
resveratrol, reduced symptoms of dementia. Resveratrol has some of the same
effects as caloric restriction, which in rodent models may mitigate AD by
improving glucose metabolism.
The
mechanisms of action of resveratrol are multifold, including increasing
autophagic and lysosomal clearance of Aβ. Specifically, resveratrol can
activate autophagy via its effects on both sirtuin 1 (SIRT1)-mediated
transcriptional regulation and mTOR-dependent signaling pathways. Resveratrol
can scavenge free radicals and suppress glial activation. For example, nuclear
factor kappa-B (NF-κB) induces inflammatory responses, and its activity is
increased with aging. Resveratrol treatment can suppress Aβ-induced activation
of NF-κB in vitro. Also, resveratrol decreases lipopolysaccharide (LPS)-induced
production of inflammatory cytokines and increases release of anti-inflammatory
interleukin-10. Resveratrol can also modulate miRNAs. Resveratrol can reduce LPS-induced
upregulation of pro-inflammatory miR-155 and upregulate anti-inflammatory
miR-663.
The
authors briefly describe three clinical publications, relating to two human trials,
which evaluated resveratrol treatment for AD. It is not clear how these
articles were chosen or whether they are the only articles available. One trial
evaluated 119 patients with mild to moderate AD who were treated with
escalating doses of 500-2000 mg/day resveratrol or placebo for 52 weeks. The
primary publication from this trial reported that resveratrol reduced Aβ in the
plasma and cerebral spinal fluid compared with placebo, indicating that
resveratrol can cross the blood-brain barrier; however, decline in brain volume
was quicker in the resveratrol group. A second publication regarding a subset
of the participants in that study [incorrectly cited in this review] reported
reduced markers of neurodegeneration and reduced decline in cognitive tests in
the resveratrol group. The third study evaluated 18 patients with mild
cognitive impairment who were treated with 150 mg resveratrol for 48 weeks and
concluded that resveratrol improved cognition and innate immune function. No
significant adverse effects were reported.
The
authors conclude that resveratrol may be able to prevent/treat AD by improving
autophagic activity, thereby reducing Tau hyperphosphorylation (which leads to
neurofibrillary tangles), neuroinflammation, and Aβ accumulation. However, the exact
molecular mechanisms are unknown.
The
study was funded by the National Natural Science Foundation of China; the
Natural Science Foundation from Science and Technology Department of Hubei
Province, China; a grant from the Donghu Scholar Program from Wuhan Sports
University to author Kou; the Chutian Scholar Program, Hubei Superior
Discipline Group of Physical Education and Health Promotion, and Outstanding
Youth Scientific and Technological Innovation Team from Hubei Provincial
Department of Education; and a grant from the Innovative Start-Up Foundation
from Wuhan Sports University to author Chen. The authors declare no conflict of
interest.
—Heather S. Oliff,
PhD
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