Preventing and Reversing “Microglia-Aging” by Nature Materials for Slow Brain-Aging. J Neurol Disord 2:143.
Zhou Wu1#*, Aiqin Zhu2#, Shizheng Wu2 and Hiroshi Nakanishi1*
1Department of Aging Science and Pharmacology, Faculty of Dental Science, Kyushu University, Fukuoka 812-8582, Japan
2Institution of Geriatric Qinghai Provincial Hospital, Shining 810007, China
#Zhou Wu and Aiqin Zhu contributed equally to this work
- Corresponding Authors:
- Zhou Wu
Department of Aging Science and Pharmacology
Faculty of Dental Science, Kyushu University
Fukuoka 812-8582, Japan
E-mail: [email protected]
- Hiroshi Nakanishi
Department of Aging Science and Pharmacology
Faculty of Dental Science, Kyushu University
Fukuoka 812-8582, Japan
E-mail: [email protected]
Received November 11, 2013; Accepted December 03, 2013; Published December 05, 2013
Citation: Wu Z, Zhu A, Wu S, Nakanishi H (2013) Preventing and Reversing “Microglia-Aging” by Nature Materials for Slow Brain-Aging. J Neurol Disord 2:143. doi: 10.4172/2329-6895.1000143
Copyright: © 2013 Wu Z, et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
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Abstract Mitochondrial DNA (mtDNA), which encodes components of the mitochondria electron transfer complexes, is highly susceptible to damage produced by reactive oxygen species (ROS), due to its close proximity to ROS generated through the respiratory chain and the paucity of protective histones. Accumulation of mtDNA damages during aging result in the reduced expression of the mitochondria electron transfer complexes, especially complex I. The resultant reduced activity of complex I further increases the generation of ROS, forming a vicious cycle. During aging, the accumulation of oxidative mtDNA damages is prominently found in the brain resident microglia. Increased intracellular ROS, in turn, drives microglia to provoke excessive neuroinflammation in the aged brain through activation of nuclear factor-κB (NF- κB). Hypoxia activates microglia to induce the generation of mitochondria-derived ROS and the subsequent activation of NF-κB signaling pathway to produce pro-inflammatory mediators, which impairs the cognitive functions. Propolis, a resinous substance produced by honeybees, significantly inhibits the hypoxia-induced neuroinflammatory responses by microglia. Furthermore, propolis and Ratanasampil, a traditional Tibetan medicine, improve the cognitive functions of the people who are living at high altitude. Considering that the daily exposure to hypoxia is one of risk factors for the aging-related cognitive impairments, these pharmacological approaches that prevent and reverse “microglia-aging” may become a most promising future research avenue for preventing the aging-related cognitive impairments.
Cognitive impairments; Microglia; Oxidative
mitochondrial DNA damage; Nature materials; Neuroinflammation
AD: Alzheimer’s Diseases; IL-1β: Interleukin-1β;
Aβ: amyloid-κ; LTP: long-Term Potentiation; NF-κB: Nuclear Factor-
κB; RNSP: Ratanasampil; ROS: Reactive Oxygen Species; TNF-α:
Tumor Necrosis Factor-α; TGF-β1: Transforming Growth Factor-β1
By the year 2030, roughly 20% of the population will be over 65
years of age in the world . As the mean life expectancy continues
to increase, it is an urgent issue to understand aging accelerators that
are responsible for cognitive impairments associated with normal
aging and Alzheimer’s disease (AD). Better understanding of aging
accelerators will help to invent the strategies for preventing the agerelated
cognitive impairments. Microglia, the resident mononuclear
phagocyte population in the brain, are activated either chronically
or pathologically to influence the neuronal environment. We have
provided evidence that the excessive reactive oxygen species (ROS)
and pro-inflammatory mediators produced by microglia cause
neuroinflammation during aging . On the other hand, hypoxia
can drive microglia to generate ROS [3-7], resulting in NF-κBdependent
excessive production of pro-inflammatory mediators,
including interleukin-1β (IL-1β), tumor necrosis factor-α (TNF-α)
and interleukin-6 (IL-6) [8-12]. Furthermore, microglia-mediated
neuroinflammation is closely associated with AD pathogenesis ,
because overproduction of pro-inflammatory mediators by microglia
triggers neuroinflammatory responses to promote neuronal damages
and deposition of amyloid-β (Aβ) [14,15]. On the other hand, antiinflammatory
agents improve cognitive functions in AD [16,17].
Recently, we have found that propolis, a resinous substance produced by
honeybees as a defense against intruders, inhibits the hypoxia-induced
production of pro-inflammatory mediators by microglia through
inhibiting the generation of mitochondria-derived ROS and the
subsequent activation of NF-κB signaling pathway . Furthermore,
propolis improves the cognitive functions of the people living at the high altitude . On the other hand, Ratanasampil (RNSP), a
traditional Tibetan medicine composing 70 nature herbal materials,
improves the cognitive functions in mild-to-moderate AD patients
living at high altitude through reducing the levels of pro-inflammatory
mediators and deposition of Aβ . In this review, we will highlight
and discuss our proposed concept of “microglia-aging”, which refers
to the concept that microglia are the most potent aging accelerators in
the brain, in cognitive impairments associated with normal aging and
AD. We will also provide a scope that nature materials could provide
significant benefits in elderly people with mild-to-moderate cognitive
Microglia as Potent Aging Accelerators of The Brain:
There is considerable variability among individuals in the extent
of decline in the cognitive functions . It is noted that the cognitive
functions in elderly people are severely impaired during infection ,
surgery  or psychological stress , thus indicating that brain is
sensitive to systemic challenges during aging [19,23-25]. Microglia, the resident mononuclear phagocytes in the brain, is activated chronically
to influence the neuronal environment during aging . Perry et al.
 first provided the concept of “primed microglia” [26-28]. Primed
microglia is characterized by shortened processes and the increased
expression of cell surface antigens similar to activated microglia, but
they are devoid of the ability to secrete pro-inflammatory molecules.
Systemic inflammatory signals activate primed microglia to provoke
exaggerated neuroinflammation in comparison to normally activated
non-primed microglia. The basal levels of pro-inflammatory mediators
are increased during aging, leading to enhanced lipopolyssacharide
(LPS)-induced sickness behavior in the aged animals. These
observations suggest that microglia in the aged brain are primed and
over-reacted to systemic challenges [29-33]. More recently, the mean
level of IL-1β secreted by primary cultured microglia prepared from
the aged brains is significantly higher than that from the young brains
[12,29,34]. These observations further support our proposed concept of
“microglia-aging” [2,35] (Figure 1).
Figure 1: Schematic representation of preventing and reversing “Microglia-Aging” by propolis and RNSP. Increased microglial mitochondria-derived
ROS induce neurodegeneration and neuroinflammation through activation of NF-κB signaling pathway, leading to cognitive impairments in elderly
people. Increased microglial cathepsin B, a lysosomal cysteine protease, is also involved in excessive neuroinflammation during aging . Nature
elements, including propolis and RNSP, prevent and reverse “Microglia-Aging” to improve cognitive functions.
The complex learning paradigms have revealed that the brain
is changed structurally and functionally even in healthy middleaged
individuals (over 50 years in human) . The prefrontal white
matter volume is significantly decreased even in the middle-age
. Furthermore, using adjuvant arthritic rats, an animal model of
stable chronic systemic inflammatory disease, we have found that
microglia induce an age-dependent differential responses to chronic
systemic inflammatory challenges [38-40]. In the young adult rats,
microglia produces anti-inflammatory mediators, including IL-10 and
TGF-β1, during chronic systemic inflammation. In contrast, microglia
produces excessive IL-1β, but less IL-10 and TGF-β1 in the middleaged
rats [41-43]. These observations strongly suggest that microglia
can be primed even in the middle-age and over-react to chronic
systemic inflammation. Furthermore, oxidative mitochondrial DNA
(mtDNA) damages are prominently found in microglia, suggesting
that over production of ROS can be a cellular mechanism for priming
of microglia after systemic inflammatory challenges [2,29]. The
primed microglia cannot be reversed to a ground state of quiescent
central housekeeping function, thus suggesting that “microglia-aging”
is associated with disappearance of their abilities for maintaining
homeostasis in microenvironment of the brain .
Acceleration of “Microglia-Aging” during Hypoxia
Brain is highly susceptible to being damaged by hypoxia because
of its high demand for oxygen supply . Function as the resident
innate immune cells in the brain, microglia constitute the first line of
defense against brain insults [45,46]. Hypoxia is generally accepted
as the neuroinflammatogens in the brain, because hypoxia activates
microglia to provoke excessive secretion of pro-inflammatory
mediators, including IL-1β, TNF-α and IL-6 [7-9,12]. We have
previous found that excessive production of ROS due to the increased
oxidative mtDNA damages in microglia is responsible for exaggerated
neuroinflammatory responses in the aged animals after treatment
with LPS, because the increased intracellular ROS level activates NF-
κB signaling pathway which regulates the expression of several proinflammatory
mediators . Hypoxia can drive microglia to generate
ROS [3-6], and we have recently found that hypoxia activates NF-κB
signaling pathway to induce exaggerated inflammatory responses by
microglia  (Figure 1).
The brain is highly vulnerable to hypoxic stress due to its high
oxygen requirement and therefore, low oxygen availability at high
altitudes results in cognitive impairments . High altitude-induced
cognitive impairments draw a special concern because this problem compromises mental performance [48,49]. We have previously
reported that higher number of elderly people living at high altitude
suffers from declines in memory and cognitive functions in comparison
to that of elderly people living at the ground level . A similar decline
in memory arising from hypoxic exposure has been also reported in
experimental animals . More recent observation shows that high
altitude-exposure deteriorates mainly attention, perception, judgment
and working memory .
Stroke is the most common form of hypoxia-ischemic brain injury.
In the western world, over 70% of individuals experiencing a stroke
is over 65 years of age. Since life expectancy continues to grow, the
absolute number of individuals with stroke will further increase in
the future . Activation of NF-κB pathway is involved in hypoxiaischemic
brain injury [53-55], and microglia are clarified as the major
cell population leading to NF-κB-dependent up-regulation of proinflammatory
mediators, including IL-1β and TNF-α during stroke
The chronic hypoxia contributes to the onset and progression
of AD [12,58,59], because hypoxia activates microglia to produce
pro-inflammatory mediators, including IL-1β TNF-α and IL-6 [7-9,12]. Microglia-mediated neuroinflammatory responses are closely
associated with AD pathogenesis , because pro-inflammatory
responses mediated by microglia promote neuronal cell damage
and excessive Aβ deposition [13,60]. It is also known that microgliamediated
neuroinflammatory responses promote cognitive deficits in
AD patients [61,62]. Taken together, hypoxia activates NF-κB signaling
pathway to accelerate cognitive impairments through promoting
It is well known the close link between hippocampal functions and
cognitive functions . Therefore, we will discuss how “microgliaaging”
impact on cognitive functions. Hippocampal long-term
potentiation (LTP) is widely accepted as a cellular basis of learning
and memory . The exceeded expression levels of pro-inflammatory
mediators in the hippocampus are associated with impairment of LTP
[65-67]. In particularly, IL-1β potently impairs the formation of the
CA1 region  and the dentate gyrus of the hippocampus [69,70].
Recently, we have found that the hippocampal LTP is significantly
impaired in the middle-aged, but not young adult, rats during chronic
systemic inflammation .
Preventing and Reversing “Microglia-Aging” by Nature
There is increasing evidence that nature materials can provide
significant benefits in dementia by their traditional usages . Propolis has relevant therapeutic properties that have been used since ancient
times. The chemical composition of propolis depends on the local floral
at the site of collection [73-75]. In addition to the fact that propolis
has anti-oxidative and anti-inflammatory effects [76-78], we recently
provided the first evidence that propolis can significantly inhibit the
secretion of IL-1β, TNF-α and IL-6 by microglia through inhibition of
the activation of NF-κB signaling pathway . Furthermore, propolis
significantly inhibits oxidative mtDNA damages, which are responsible
for the induction of excessive ROS and the subsequent activation of
NF-κB signaling pathway. Moreover, propolis significantly inhibits
the increased expression of 8-oxo-deoxyguanosine, a biomarker
for oxidative DNA damages , which was observed mainly in the
mitochondria of cortical microglia after hypoxia. On the other hand,
effects of RNSP on the oxidative mtDNA damages are to be elucidated
in future studies. With the line of our previous observations that oxidative mtDNA damages, in turn, impair the respiratory chain,
forming a vicious cycle to promote the ROS generation , propolis
may prevent and reverse “microglia-aging” through its anti-oxidant property [76-80] (Figure 1).
People living in Qinghai-Tibet Plateau experience chronic hypoxia
at high altitude. Current medical researches on the age-related cognitive
impairment spay a special attention on this area, because higher
number of the elderly population suffers from declines in memory and
cognitive functions [81,82]. RNSP, one of the most important Tibetan
medicines, is composed of 70 nature herbal materials . RNSP is used
to treat cerebrovascular diseases such as cerebral hemorrhage, cerebral
infarction, epilepsy and brain concussion. Recently, clinical studies
have revealed that RNSP has sedative and anti-convulsant effects,
improves memory and circulation, and reduces platelet aggregation
and antithrombotic properties [84,85]. Our previous studies have also
showed that RNSP improves learning and memory in a mouse model
of AD (Tg2576) [86,87] and improves cognitive functions in mild-tomoderate
AD patients living at high altitude . Furthermore, our
preliminary clinical studies for people living at high altitude show that
the propolis-treated elderly group obtained significantly higher scores
of cognitive tests than the non-treated elderly group . Moreover,
both RNSP and propolis reduce the mean level of pro-inflammatory
mediators, including IL-1β, TNF-α and IL-6 in the activated
macrophages as well as in serum of peripheral blood of human,
indicating that they also ameliorate systemic inflammatory challenges
[18,88]. As we have discussed above, microglia can be primed even
in the middle-age to sensitize to systemic inflammatory challenges.
Therefore, the pharmacological approaches using nature materials that
prevent and reverse “microglia-aging” may become a most promising
future research avenue for improving cognitive functions of elderly
people (Figure 1).
We provide the scope that “microglia-aging” works as a brainaging
accelerator, which is associated with cognitive impairments
during normal aging and AD. Propolis and RNSP, nature materials, can improve cognitive functions of elderly people through preventing
and reversing “microglia-aging” (Figure 1).
This work was partly supported by Yamada Research Grant to Zhou Wu
(No.0124) and Science Research Foundation for the Returned Scholars, Ministry
of Human Resources and Social Security of the People’s Republic of China to Aiqin
Zhu (No 2012-258).
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