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Initial loss of NE/LC neurons resulted from either LPS or DSP-4 injection renders neurons in the NE neuron-innervated regions more susceptible to inflammation-related damage. In normal condition (Left), NE released from the presynaptic terminals of LC/NE neurons performs multiple functions through different ways of transmission. During synaptic transmission, released NE functions as a neuromodulator by directly acting on postsynaptic β2-receptors to modulate the function of postsynaptic neurons. In volume transmission, extra-synaptic NE, diffused out of the synapse or released from dendrites, can act on other neighboring cells, such as microglia. NE exerts anti-inflammatory and neuroprotective functions through the inhibition of microglial NOX2. In pathological condition (Right), reduced NE release from LC/NE neurons not only disrupts the synaptic transmission, but also renders surrounding microglia prone to activation to release proinflammatory immune factors, leading to neuronal damage. Thus, we hypothesize that dysfunction of LC/NE neurons after LPS or DSP-4 injection renders neurons more sensitive to inflammation/oxidative insults and initiates neurodegeneration.
Source publication
The role of norepinephrine (NE) in the pathogenesis of Parkinson’s disease (PD) has not been well investigated until recently. The purpose of this perspective article is to review evidence supporting the idea that dysfunction of the locus coeruleus (LC)/NE system in the brain may be fundamentally linked to the pathogenesis of PD. Compelling evidenc...
Citations
... Abnormal depositions of aggregated α-syn were found in the bilateral frontal cortex (FrC), somatosensory cortex (Ctx), hypothalamus (Hypo-thal), brain stem (BS), and cerebellum (Cere). In addition, it was found that the immune-inflammatory system played a critical role in the communication between the brain and intestine [26,27], and microglia and astrocytes were important for the regulation of neuroinflammation [28]. In the present study, increased Ionized calcium-binding adapter molecule 1 (Iba1) and glial fibrillary acidic protein (GFAP) expression as well as the ratio of reactive Iba1/GFAP-positive cells were found in the SN pars compacta (SNc) of the rats injected with intestine or vagus lysate, which showed prominent microglial activation and astrocytic gliosis, as well as a loss of tyrosine hydroxylase (TH)-positive dopaminergic neurons. ...
Parkinson’s disease (PD) is characterized by the selective loss of dopaminergic neurons in the midbrain and the pathological accumulation of misfolded α-synuclein (α-syn) in the brain. A growing body of evidence suggests that the formation of misfolded α-syn and aggregation may begin in the peripheral nervous system, specifically the enteric nervous system, and then propagate to the central nervous system via the vagus nerve. However, the PD-like neuropathology induced by the intestine and vagus nerve extracts is rarely investigated. In this work, we injected lysates of the intestine and vagus obtained from a diagnosed PD patient, which contained abnormal α-syn aggregates, into the rat striatum unilaterally. Strikingly, such an injection induced dopaminergic neurodegeneration and α-syn depositions in the striatum, substantia nigra, and other brain regions, including the frontal cortex, somatosensory cortex, hypothalamus, brain stem, and cerebellum. Moreover, significant activation of microglia and the development of astrogliosis were observed in the substantia nigra pars compacta of the injected rats. These findings provide essential information for our understanding of PD pathogenesis, as we established for the first time that the α-syn aggregates in the intestine and vagus of a PD patient were sufficient to induce prion-like propagation of endogenous α-syn pathology in wild-type rats.
... Inflammatory circumstances generally cause intestinal bacteria to become more pathogenic and less symbiotic, thereby aggravating inflammation and raising the possibility of sustained immunological reactions in the gut [49]. In a cohort study, Villumsen et al. [50] found individuals troubled with IBD are more susceptible to PD. Inflammation is a well-known feature of PD [51]. It has been proposed that this inflammation may be triggered by a disruption in the intestinal barrier, which exposes the system to inflammatory microbial compounds such LPS, a component of bacterial cell walls [52]. ...
The scientific and medical communities are becoming more aware of the substantial relationship between the function of the central nervous system (CNS) and the state of the gut environment. Parkinson's disease (PD) is a neurodegenerative disorder that affects the nigrostriatal pathway in the midbrain, presenting not only motor symptoms but also various non-motor manifestations, including neuropsychiatric symptoms and gastrointestinal (GI) symptoms. Over time, our knowledge of PD has progressed from the detection of midbrain dopaminergic deficits to the identification of a multifaceted disease with a variety of central and peripheral manifestations, with increased attention to the intestinal tract. Accumulating evidence has revealed that intestinal disorders are not only the peripheral consequence of PD pathogenesis, but also the possible pathological initiator decades before it progresses to the CNS. Here, we summarized recent research findings on the involvement of the intestinal environment in PD, with an emphasis on the involvement of the intestinal barrier, microbiome and its metabolites, inflammation, and enteric glial cells.
... Nurr1, also known as NR4A2/NOT/TINUR, is a member of the orphan nuclear receptor family 4 (NR4A), necessary for the mdDA neurons' development, maturation, and functional maintenance [46,69,70]. It is also involved in neuroprotection and neuroinflammation regulation by inhibiting pro-inflammatory factors in microglial and astrocytes cells [71][72][73]. Notably, in mdDA neurons, the decreased levels of Nurr1 were characterized during aging, which may be related to the increased morbidity of PD [74,75]. Furthermore, Nurr1 is required for neuronal plasticity remodeling. ...
The meso-diencephalic dopaminergic (mdDA) neurons regulate various critical processes in the mammalian nervous system, including voluntary movement and a wide range of behaviors such as mood, reward, addiction, and stress. mdDA neuronal loss is linked with one of the most prominent human movement neurological disorders, Parkinson’s disease (PD). How these cells die and regenerate are two of the most hotly debated PD research topics. As for the latter, it has been long known that a series of transcription factors (TFs) involves the development of mdDA neurons, specifying cell types and controlling developmental patterns. In vitro and in vivo, TFs regulate the expression of tyrosine hydroxylase, a dopamine transporter, vesicular monoamine transporter 2, and L-aromatic amino acid decarboxylase, all of which are critical for dopamine synthesis and transport in dopaminergic neurons (DA neurons). In this review, we encapsulate the molecular mechanism of TFs underlying embryonic growth and maturation of mdDA neurons and update achievements on dopaminergic cell therapy dependent on knowledge of TFs in mdDA neuronal development. We believe that a deeper understanding of the extrinsic and intrinsic factors that influence DA neurons’ fate and development in the midbrain could lead to a better strategy for PD cell therapy.
... Under inflammatory or neurotoxic conditions, glia generally turns into a harmful phenotype accompanied by the release of EVs, contributing to the increase of DAergic neuron vulnerability and the exacerbation of neuronal death (Wang et al., 2021). Results from the α-synuclein overexpression mouse model indicate that the abnormity accumulated α-synuclein can alter the pro-inflammatory gene expression profile in the glial. ...
Extracellular vesicles (EVs), as nano-sized vesicles secreted by almost all cells, have been recognized as the essential transmitter for cell-to-cell communication and participating in multiple biological processes. Neurodegenerative diseases (ND), such as Alzheimer’s disease, Parkinson’s disease, and amyotrophic lateral sclerosis, share common mechanisms of the aggregation and propagation of distinct pathologic proteins among cells in the nervous systems and neuroinflammatory reactions mediated by glia during the pathogenic process. This feature indicates the vital role of crosstalk between neurons and glia in the pathogenesis of ND. In recent years, glia-derived EVs have been investigated as potential mediators of signals between neurons and glia, which provides a new direction and strategy for understanding ND. By a comprehensive summary, it can be concluded that glia-derived EVs have both a beneficial and/or a detrimental effect in the process of ND. Therefore, this review article conveys the role of glia-derived EVs in the pathogenesis of ND and raises current limitations of their potential application in the diagnosis and treatment of ND.
Objectives:
Exercise is assumed to attenuate age-related neuronal apoptosis, but the detailed mechanism(s) is not fully understood. α1-adrenergic receptors (ARs) can either trigger or suppress apoptosis, therefore, here we determined the impact of treadmill exercise on the expression of the apoptosis regulatory proteins as well as α1-AR subtypes α1A- and α1B-ARs, in order to elucidate a possible association between apoptosis and the hippocampal expression of α1-ARs in aged male rats.
Methods:
Twenty-one male Wistar rats were divided into 3 groups (n=7): young control, aged sedentary, and aged + exercise. Western blot for α1A- and α1B-ARs as well as pro-(Bax and p53) and anti-apoptotic (Bcl2) proteins was conducted. An 8-week regular moderate-intensity treadmill exercise intervention was carried out in exercise group.
Results:
In aged rats, α1A-AR expression in the hippocampus was significantly increased, and exercise markedly prevented this event. While α1B-AR expression was no altered with aging, a marked reduction in α1B-AR level was detected in exercise group when compared to aged group. Furthermore, pro-apoptotic protein levels of Bax and p53 were upregulated and anti-apoptotic protein Bcl2 was downregulated in the aging hippocampus, but could be reversed by treadmill exercise. In the present research, exercise-induced reduction in α1A- and α1B-ARs was associated with an obvious downregulation of Bax/Bcl2 ratio in aged rats, suggesting that exercise may inhibit apoptosis through regulating α1-ARs, particularly α1A-AR.
Conclusions:
Our study suggests that manipulations attenuating α1-AR activity, including nonselective α1-adrenergic antagonists, may protect against hippocampal neurodegeneration in aging brains.
