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The Role of Acupuncture Improving Cognitive Deficits due to Alzheimer’s Disease or Vascular Diseases through Regulating Neuroplasticity
Shaozhen Ji
,1,2,3 Jiayu Duan,1,4 Xiaobing Hou,5 Li Zhou,6 Weilan Qin,6 Huanmin Niu,5 Shuyun Luo,5 Yunling Zhang,7 Piu Chan,2,3 and Xianglan Jin11Department of Neurology, Dongfang Hospital, Beijing University of Chinese Medicine, Beijing 100078, China
2Department of Neurobiology, Xuanwu Hospital of Capital Medical University, Beijing 100053, China
3National Clinical Research Center for Geriatric Disorders, Capital Medical University, Beijing 100053, China
4Beijing University of Chinese Medicine, Beijing 100029, China
5Department of Neurology, Beijing First Hospital of Integrated Chinese and Western Medicine, Beijing 100039, China
6Department of Acupuncture and Moxibustion, Dongfang Hospital, Beijing University of Chinese Medicine, Beijing 100078, China
7Xiyuan Hospital, China Academy of Chinese Medical Sciences, Beijing 100091, China
Abstract
Dementia affects millions of elderly worldwide causing remarkable costs to society, but effective treatment is still lacking. Acupuncture is one of the complementary therapies that has been applied to cognitive deficits such as Alzheimer’s disease (AD) and vascular cognitive impairment (VCI), while the underlying mechanisms of its therapeutic efficiency remain elusive. Neuroplasticity is defined as the ability of the nervous system to adapt to internal and external environmental changes, which may support some data to clarify mechanisms how acupuncture improves cognitive impairments. This review summarizes the up-to-date and comprehensive information on the effectiveness of acupuncture treatment on neurogenesis and gliogenesis, synaptic plasticity, related regulatory factors, and signaling pathways, as well as brain network connectivity, to lay ground for fully elucidating the potential mechanism of acupuncture on the regulation of neuroplasticity and promoting its clinical application as a complementary therapy for AD and VCI.
1. Introduction
As the population ages, the prevalence of dementia is increasing worldwide with an annual incidence of nearly 10 million [1], which leads to threats and challenges to global health and wellbeing. Dementia is characterized as a syndrome with myriad and complex causes, including primary neurologic, neuropsychiatric, and medical conditions and genetic and environmental factors [2, 3]. In the elderly, neurodegenerative dementias are most common [2], among which Alzheimer’s disease (AD) is believed to be the leading cause of dementia, and vascular cognitive impairment (VCI) is the second utmost cause [4, 5]. Unprecedented advancements have been made in molecular neuroimaging, clinicopathologic correlation, and the development of novel biomarkers in recent decades. However, effective therapeutics remain limited and even absent to date [4, 5]. Acupuncture, as one of complementary therapies for AD and VCI, is gradually applied to alleviate suffering, aggressively treating contributing symptoms and improving overall quality of life [6–10]. However, the underlying mechanisms remain elusive.
Neuroplasticity refers to the capacity of the nervous system to adapt to internal and external environmental changes by reorganizing its structure, function, and connections [11–14], which occurs at various levels of the nervous system from tissue to cellular to molecular [13]. It is known that dysregulated or disrupted neuroplasticity is implicated as a pathological mechanism in AD [15] and VCI [16]. Furthermore, some treatments that stimulate or modulate neuroplasticity have been indicated as effective in improving cognition [12, 17, 18], and might be potential therapy in cognitive impairments such as AD and VCI.
Acupuncture signals are recognized as a potent form of sensory stimulation that ascend mainly through the spinal ventrolateral funiculus to the brain [19]. The mechanisms of acupuncture-mediated neuroplasticity have recently attracted increased interest. Accordingly, acupuncture modulation over several cognition- or aging-related gene expressions [20], plasticity signaling pathways [21, 22], and brain functional connectivities [23] has been studied. Herein, we review the application of different protocols of acupuncture in animal models and humans, and their effectiveness on neuroplasticity in various sections: neurogenesis and gliogenesis, synaptic plasticity, related proteins and signaling pathways, and brain network connectivity. This review is aimed at laying the ground for elucidating the potential mechanism of acupuncture on AD and VCI to promote its clinical application as a complementary treatment.
2. Neurogenesis and Gliogenesis
The proliferation and differentiation of neurons and glial cells, also known as neurogenesis and gliogenesis, contribute to some neurorepair and improve brain function [24, 25]. Many previous results demonstrated that cerebral amyloidosis in AD mouse models caused neuronal proliferation inhibition and marked gliogenesis [26–28], and that stroke could trigger striatal and cortical neurogenesis and gliogenesis in murine models [29]. Mounting evidence indicates that adult hippocampal neurogenesis is implicated in cognitive processes, and that neurogenesis deficits may impair learning and memory. In states of brain injury such as AD and VCI, compensatory neurogenesis and gliogenesis mediate a balance between initial injury processes and endogenous repair processes [24]. Regulation of neurogenesis and gliogenesis is possibly associated with improving cognitive impairment and, consequently, may be attractive therapeutic targets for AD and VCI.
It is known that neurogenesis in the adult mammalian brain mostly takes place in specific brain regions harboring adult neuro stem and precursor cells, such as the subgranular zone (SGZ) of the hippocampal dentate gyrus (DG) and the ventricular/subventricular zone (VZ/SVZ) of the lateral ventricles [25]. Cognitive impairment due to AD or ischemic injury is recognized as partly related with neuron loss, impairment of cell proliferation, and imbalance between neuron loss and proliferation in the above regions [30]. Some studies showed that both manual acupuncture (MA) and electroacupuncture (EA) could ameliorate the learning and memory deficits of AD mice models through inducing the enhancement of neuron proliferation and migration in hippocampal DG and VZ/SVZ [31–33]. And the effect of MA and EA on improving cognitive dysfunction through the proliferation and differentiation of hippocampal neuro stem cells (NSCs) was also identified in murine models for vascular dementia (VaD) [34–36]. In addition, neurogenesis could take place in other brain areas in pathological conditions, such as the cortex [37], where the promotion of neurogenesis related to EA was also detected in the transgenic mice model for AD [33].
VCI is recognized to be associated with pathological changes in white matter degeneration and demyelination [38]. Oligodendrocyte (OL), as one predominant cell type in white matter, mediates myelination that is an essential process for the appropriate propagation of action potentials along axons [39]. Myelination participates in the restoration of damaged white matter in the adult brain [40], which may provide potential utility for the treatment of VCI. In a mouse model of VaD, EA was indicated to enhance the differentiation of oligodendrocyte precursor cells (OPCs) into mature OLs and ameliorate white matter damage in the corpus callosum (CC) [41]. Moreover, astrocytes also perform critical impacts on promoting neovascularization, regulating neuronal activity, and supporting synaptogenesis and neurogenesis, which may influence recovery following ischemic lesion [39, 42]. Experimental studies have reported that acupuncture was able to influence the proliferation and differentiation of astrocytes; however, the results were discrepant. One study revealed that MA was able to inhibit astrocyte activation and proliferation in VaD rat models [36]. Conversely, Kim et al. found that EA stimulation could induce NSCs differentiated into astrocytes in a VaD mouse model [35]. These results may be caused by differential acupoints or acupuncture methods. The differential influence of the acupuncture method (i.e., MA vs. EA) on neurogenesis has been demonstrated. And one study found that MA vs. EA stimulation at the same acupoints might induce differential cell proliferation and neuroblast differentiation in healthy rats [43]. And further investigation of the compared impact of differential acupuncture methods and acupoints on gliogenesis in AD and VCI models is required.
In addition to the direct effect on endogenous neurogenesis and gliogenesis, acupuncture was able to promote the survival, proliferation, migration, and differentiation of exogenous NSCs in the hippocampal microenvironment by regulating components of the cerebral microenvironment [44] or the related cytokine levels [45] in an AD mice model. All these findings demonstrated the influence of acupuncture on endogenous and exogenous neurogenesis and gliogenesis in AD and VCI, which deepen our understanding of acupuncture modulating neuroplasticity. There remain some limitations and even discrepancies in these results possibly caused by acupoints or models or observation times, or even acupuncture methods (i.e., MA vs. EA). And the mechanisms underlying the impact of acupuncture on neurogenesis and gliogenesis in different states, especially molecular mechanisms, need to be investigated.
3. Synaptic Plasticity
Synapses, the most sensitive and plastic structures, are directly involved in the integration and transfer of information within the neuro system. Previous studies demonstrated that synapse loss and dysfunction was a key feature in AD [46] and VCI [47] and positively correlates with cognitive damage. Impaired dendritic structure, spine density, and synaptic ultrastructure of neurons have been identified in brain tissue of AD patients and murine models, caused by soluble amyloid beta (Aβ) in the hippocampus [48, 49]. And ischemia-induced synapse reduction was also recognized to be the major pathological causes of VaD [50]. Synaptic plasticity, also defined as activity-dependent synaptic modifications of the strength of synaptic connections, is widely recognized to be fundamental to the formation and maintenance of learning and memory [51]. Synaptic plasticity in the neuro network, an important basis for cortical plasticity, is associated with learning and memory and sensorimotor dysfunction and recovery [51, 52]. Synaptic plasticity mainly includes modulation of the morphological structure of synapses and the synaptic strength and transmission, in which some synaptic protein markers, neurotransmitters, and receptors participate. Recently, modulation of synaptic plasticity is believed to be a promising approach for treating AD and VCI.
Synapse-structure parameters, such as synaptic curvatures, the width of the synaptic cleft, and the thickness of the postsynaptic density, are proposed to be important indicators that reflect synaptic morphological plasticity and greatly affect synaptic transmission [53]. Many studies revealed that MA and EA treatments had positive effects on the recovery of the learning and memory abilities not only in AD rat models but also in VCI, through increasing synaptic curvatures, decreasing the width of synaptic clefts, and thickening the postsynaptic densities in the hippocampus [49, 54]. In addition, MA was able to reverse the learning and memory impairments in AD mice models through enhancing the conjunction among the synapses and promoting synaptic formation [20] and regeneration [55], reducing ultrastructural degradation of synapses [56], and increasing the number and length of dendrites [57] and neurite fibers [58].
Long-term potentiation (LTP) and long-term depression (LTD) are considered as two indicators and forms of synaptic transmission [59]. As a cellular model of synaptic plasticity, LTP is the long-lasting enhancement in signal transmission between two neurons after synchronous stimulation associated with memory formation and storage, reflecting an increase of synaptic strength [60]. LTD is relevant to memory integration, forgetting, and recovery of LTP production at desaturation state [61]. And converging studies supported a crucial role of LTD in some types of learning and memory and in situations where cognitive demands require a flexible response [59]. Many electrophysiological studies showed that acupuncture could apparently improve the recovery from cognitive deficits by promoting LTP and/or LTD [61–63] and preventing or restoring the impaired LTP [64–69] in AD or VCI rat models. In addition to LTP and LTD, EA could also ameliorate the synaptic transmission by raising the slope of excitatory postsynaptic potential (EPSP) and the amplitude of population spikes (PS) in an AD mouse model [70].
Synaptophysin (SYN) is a major integral membrane protein of the presynaptic vesicle, and postsynaptic density 95 (PSD-95) and growth-associated protein 43 (GAP-43) are postsynaptic markers [71]. As important protein markers of regeneration and remodeling, they are widely found in all nerve terminals and used for quantifying the number of axon terminals, reflecting the occurrence, density, and strength of synapses [49, 72]. Many previous studies reported reduced expression of SYN and PSD-95 in the hippocampus in AD and VaD [73, 74]. It was demonstrated that acupuncture was able to promote synapse-structure damage rehabilitation by upregulating the expression of SYN [44, 54, 55], PSD-95 [56, 75, 76], and GAP-43 [77] to improve the learning and memory abilities of AD and VCI murine models.
Furthermore, accumulated evidence indicates that the effect of acupuncture on modulating synaptic structure and function in AD and VCI is achieved by changing the releasing of the presynaptic neurotransmitter or the function of the postsynaptic receptor [67, 68, 78]. As one of the major neurotransmitters, dopamine (D) plays an essential role in modulating hippocampal LTP and memory processes [79, 80]. Ye et al. found that MA could activate D1/D5 receptors to ameliorate cognitive function and LTP impairments in VaD rats [67]. The central cholinergic pathway and the norepinephrine- (NE) adrenergic receptor (AR) system are known for their critical roles in learning acquisition and synaptic plasticity in the mammalian limbic system. It was demonstrated that MA not only could alleviate memory-associated decreases in the levels of choline acetyltransferase (ChAT) and restore the expression of choline transporter 1 (CHT1) as well as vesicular acetylcholine transporter (AChT), resulting eventually in the recovery of the entire cholinergic system circulation pathway [81], but also was able to enhance norepinephrine (NE) levels and the activation of β1-AR in the hippocampus [68]. In addition, γ-aminobutyric acid (GABA) is one main inhibitory neurotransmitter in the central nervous system inhibiting the excessive release of glutamate (Glu). And GABA receptor-mediated inhibitory inputs modulate hippocampal LTP [82]. EA could elevate the excitability of granule cells by decreasing GABA from interneurons, which resulted in increasing LTP [78].
Glutamate receptors (GluRs) are the main receptors of the postsynaptic neurotransmitter area and modulate synaptic plasticity; they are divided into metabotropic GluRs and ionotropic GluRs. Among the three types of ionotropic GluRs, N-methyl-D-aspartate receptor (NMDAR) is the most widely distributed regulator of synaptic plasticity, which plays an important role in inducing and maintaining LTP and LTD closely associated with learning and memory [83]. NMDARs are comprised of NMDAR subtype 1 (NMDAR1) subunits plus at least one type of NMDAR2 subunit [84]. It was reported that EA could reduce the deficit of LTP in VaD rat models via reversal of NMDAR1- and transient receptor potential vanilloid subtype 1- (TRPV1-) mediated neurotoxicity [62]. NMDAR2 seems to have complex properties, and different NMDAR2 subunits confer distinct electrophysiological and pharmacological properties on the receptors and couple themselves with opposing signaling pathways and influences on the direction of synaptic plasticity [85]. Specifically, NMDAR2A activation is beneficial for neuronal regeneration and neuroprotection, while NMDAR2B induces neurotoxicity and neuronal apoptosis [85]. One study found that EA could alleviate cognitive dysfunction caused by ischemic injury through downregulation of NMDAR2B and upregulation of NMDAR2A [86].
The effect of EA on synaptic plasticity might be related to the parameter of stimulation. One study has found that high-frequency EA may yield a stronger protective effect on hippocampal synaptic plasticity compared with low- or medium-frequency EA in AD rat models [61]. Further research focusing on ascertaining the optimum acupuncture parameter is required. Moreover, besides these mechanisms described above, many synaptic-related proteins or signaling pathways were required in maintaining synaptic structural plasticity and synaptic transmission. Investigations of synaptic plasticity-related regulatory factors and signaling mechanisms have been performed in many studies, and these are going to be described in Section 4.
4. Neuroplasticity-Related Regulatory Factors and Signaling Pathways
Multiple crucial steps are involved in the process of neuroplasticity, which include many layers of regulation, composed of both intrinsic and extrinsic mechanisms. For example, there are a number of coordinated cell-intrinsic programs and external signals involved in distinct stages of adult neurogenesis, including proliferation and lineage differentiation of NSCs, migration of neuroblasts, and integration of newborn neurons [87]. Given the important role of related factors and signaling pathways in neuroplasticity, ascertaining acupuncture’s effect on them may be vital to understanding the mechanisms of its treatment for AD and VCI.
As one of the morphogens that are critical during embryonic development of the nervous system, Notch is highly conserved and serves as niche signals to regulate the proliferation of adult NSCs [88]. The regeneration of neurons from neural progenitors may be impaired due to the abnormal elevated Notch signal pathway. EA treatment suppressed neuronal apoptosis and improved cognitive impairment in AD rat models possibly via the downregulation of an abnormal elevated Notch signaling pathway [89]. Moreover, EA also was able to enhance hippocampal NSC proliferation in VaD rat models via the activation of the Notch signaling pathway [34].
In addition to the neurotransmitters described above, the survival and synaptic integration of newly born cells are subject to regulation by neurotrophic factors. As a member of the neurotrophic factor family, the BDNF protein is synthesized as pre–pro-BDNF and cleaved intracellularly into a pro-BDNF protein encompassing two domains: the prodomain and the mature BDNF domain [90]. BDNF is actually secreted in the pro- and mature form [91], which had distinct receptors and signaling cascades resulting in opposing biological functions [92–94]. The mature BDNF preferentially binds to phosphorylated tropomyosin receptor kinase B (Trk-B) receptors leading to cell survival and differentiation as well as hippocampal LTP, whereas pro-BDNF preferentially binds to p75 neurotrophin receptor (p75NTR) leading to apoptosis and hippocampal LTD [95]. It was observed that acupuncture could upregulate the expression of Trk-B receptors and could decrease the expression level of p75NTR in AD and VaD murine models, influence the modulation and processing of the BDNF protein from pro-BDNF to mature BDNF [33, 96, 97], and eventually enhance the mRNA expression levels of mature BDNF [35, 45, 54, 81]. One clinical trial showed that combined scalp acupuncture and cognitive training could improve the cognitive function and BDNF levels of peripheral blood in patients with stroke during the recovery stage [98]. Other extrinsic factors such neurotrophin 3 (NT3), NT4, and NT5 also play an important role in the regulation of neuronal integration [99]. EA treatment has been reported to increase the expression of NT4/5 and their receptor, tyrosine receptor Trk-B, and promote OL regeneration in association with cognitive functional improvements in a VaD mice model [41]. In addition, acupuncture also could regulate intrinsic factors associated with neuronal integration. For instance, MA was demonstrated to restore the expression of cAMP-response element-binding protein (CREB) mRNA in the hippocampus of rats with cognitive impairment [81].
The typical pathological hallmarks of AD include extracellular Aβ plaques and intracellular neurofibrillary tangles (NFTs) composed of hyperphosphorylated tau proteins, both of which resulted in the loss and morphological changes of dendritic spines, directly leading to the damage of neuronal synaptic function and neuroplasticity [100]. Many studies showed that acupuncture could regulate neuroplasticity by directly reducing Aβ deposition [56, 101], and some related proteins and signaling pathways participated in this process. Glycogen synthase kinase 3 beta (GSK3β) is a serine/threonine protein kinase that plays a crucial role in AD pathogenesis, and its hyperactivity or overexpression is increasingly shown to be closely related to Aβ generation, tau hyperphosphorylation, and synaptic plasticity [102]. Inhibition of GSK3β has been indicated to increase the number of synapses and postsynaptic density thickness, and rescue the reduction of spine density in the hippocampus of an AD model. It has been revealed that EA could promote synapse-structure damage rehabilitation by downregulating GSK3β to improve the learning and memory abilities of AD rat models [49, 77]. As the downstream target of GSK3β, the reactivation of mTOR restored the acidification of the autophagy lysosome, further promoting the autophagy clearance of pathological Aβ plaque load [103]. Yu et al. found that EA rescued structural and functional synaptic plasticity impairments and memory deficits in AD rat models through the inactivation of GSK3β/mTOR signaling [21]. Moreover, β-site amyloid precursor protein cleaving enzyme 1 (BACE1) is the key protein involved in Aβ peptide generation. One study indicated that EA could downregulate the expression of BACE1 in one AD mouse model [64].
There are some regulated factors and signaling pathways directly involved in the modulation of LTP. Protein kinase A (PKA) is a predominantly positive modulator of LTP in the hippocampus and has been demonstrated to indispensably participate in the efficacy of hippocampus-based memory [104]. Tang et al. found that EA could upregulate PKA activation, enhance synaptic plasticity, and improve memory in an AD mice model [64]. The p70 ribosomal protein S6 (p70S6) kinase/ribosomal protein S6 signaling pathway has been shown to promote neuronal growth and LTP [105, 106]. One study showed reduced expression of p70S6 kinase and ribosomal protein S6 in the hippocampus of VaD rats, which suggested that the p70S6 kinase/ribosomal protein S6 pathway was involved in the pathogenesis of VaD [63]. EA was demonstrated to improve the learning and spatial memory abilities of VaD rats and facilitate LTP in the hippocampus by upregulating expression of p70S6 kinase and ribosomal protein S6 [63]. The p70S6 kinase was phosphorylated by activation of the mammalian target of rapamycin (mTOR) signal pathway, which has been shown to promote neuronal growth and LTP [107, 108]. Acupuncture stimulation has been indicated to promote neuroplasticity by regulating the mTOR signal pathway in AD or VaD rats [21, 109]. Moreover, it was reported that MA could reverse the learning and memory impairments in an AD mouse model through upregulating eukaryotic Y-box-binding protein (YB-1) expression [20], which enhanced the conjunction among the synapses and promoted synaptic formation indirectly [110]. The eukaryotic elongation factor-2 kinase/eukaryotic elongation factor-2 (eEF2K/eEF2) pathway is also associated with synaptic plasticity and its inhibition prevents synaptic failure in AD. One study showed that EA improved the synaptic function in AD by inhibiting the AMPK/eEF2K/eEF2 pathway in an AD mouse model [76].
Besides the above-related factors and signaling pathways, other mechanisms, such as oxidative stress, glucose metabolism, and inflammatory responses, were considered to play a key role in acupuncture treating AD or VCI and modulating neuroplasticity (Table 1 and Figure 1). These molecular mechanisms support acupuncture as a potentially promising therapy for the treatment of cognitive dysfunction in patients with VD or VCI.
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