Aging-related changes in RP3V kisspeptin neurons predate the reduced activation of GnRH neurons during the early reproductive decline in female mice.
Zhang Jing,Yang Lumeng,Lin Nan,Pan Xiaodong,Zhu Yuangui,Chen Xiaochun
Neurobiology of aging
Kisspeptin neurons in the rostral periventricular area of the third ventricle (RP3V) play a key role in relaying the positive feedback effects of estradiol that activate gonadotropin-releasing hormone (GnRH) neurons and drive a surge in the GnRH/luteinizing hormone (LH) level. However, the precise role of kisspeptin neurons during female reproductive senescence remains unclear. Focusing on middle-aged intact female mice with irregular estrous cycles, we found a parallel decline in c-Fos-positive kisspeptin neurons and c-Fos-positive GnRH neurons at the time of the GnRH/LH surge. Furthermore, in kisspeptin neurons, the expression of estrogen receptor α (ERα), but not progesterone receptor (PR), decreased with age. Interestingly, some kisspeptin neurons in the RP3V, but none of the GnRH neurons in the rostral preoptic area (rPOA), had a characteristic cellular senescence in middle-aged mice and old mice. These data suggest that, among the groups of neurons involved in reproductive control, the kisspeptin neurons in the RP3V are likely among the earliest to undergo aging processes and thus participate in initiating the early reproductive decline.
10.1016/j.neurobiolaging.2013.08.038
Mild clinical manifestation and unusual recovery upon coenzyme Q₁₀ treatment in the first Chinese Leigh syndrome pedigree with mutation m.10197 G>A.
Chen Zhiting,Zhao Zhenhua,Ye Qinyong,Chen Ying,Pan Xiaodong,Sun Bin,Huang Huapin,Zheng An
Molecular medicine reports
The Leigh syndrome (LS), characterized by psychomotor retardation, seizures, nystagmus, ophthalmoparesis, optic atrophy, ataxia, dystonia, or respiratory failure, is one of the most severe mitochondrial diseases. In the majority of cases, the disease is fatal and patients die before age 5. Mutation m.10197 G>A was found to relate to the severe phenotype of the Leigh syndrome. Here, we describe the first Chinese Leigh syndrome pedigree with this mutation. The proband had the characteristic brain lesions of the Leigh syndrome and presented a decrease in exercise tolerance and mild face paralysis. Sequencing the NADH dehydrogenase, subunit 3 (ND3) gene in the pedigree, revealed that the proband, as well as her unaffected brother, have a high mutant load in the ND3 gene, compared to their mother. Following one‑year treatment with the coenzyme Q10, an obvious improvement in clinical features was observed by magnetic resonance imaging (MRI) in the proband. Our study and previous reports highlight the variability of phenotypic expression of the m.10197 G>A mutation, and suggest that pathogenesis of the syndrome may be affected by a number of factors. This is the first report on successful treatment of an LS patient carrying the mutation m.10197 G>A with the coenzyme Q10, indicating that Q10 may attenuate the mitochondrial dysfunctions caused by the m.10197 G>A mutation.
10.3892/mmr.2014.2911
Tripchlorolide improves cognitive deficits by reducing amyloid β and upregulating synapse-related proteins in a transgenic model of Alzheimer's Disease.
Zeng Yuqi,Zhang Jian,Zhu Yuangui,Zhang Jing,Shen Hui,Lu Jianping,Pan Xiaodong,Lin Nan,Dai Xiaoman,Zhou Meng,Chen Xiaochun
Journal of neurochemistry
Alzheimer's disease (AD) is characterized by early impairments in memory and progressive neurodegeneration. Disruption of synaptic plasticity processes that underlie learning and memory contribute partly to this pathophysiology. Tripchlorolide (T4 ), an extract from a traditional Chinese herbal Tripterygium wilfordii Hook F, has been shown to be neuroprotective in animal models of Parkinson's disease and to improve cognitive deficits in senescence-accelerated mouse P8. In this study, we investigated the effect of T4 on cognitive decline and synaptic plasticity in five times familial AD (5XFAD) mice co-expressing mutated amyloid precursor protein and presenilin-1. Five-month-old 5XFAD mice and wild type littermates were intraperitoneally injected with T4 , 5 μg/kg or 25 μg/kg, every other day for 60 days. T4 treatment significantly improved spatial learning and memory, alleviated synaptic ultrastructure degradation, up-regulated expression of synapse-related proteins, including synaptophysin, post-synaptic density-95, N-methyl-D-aspartate receptor subunit 1, phosphorylation of calcium/calmodulin dependent protein kinase II α, and phosphorylation of cyclic AMP-response element binding protein, and promoted activation of the phophoinositide-3-kinase-Akt-mammalian target of rapamycin signaling pathway in 5XFAD mice. Accumulation of amyloid β (Aβ) may contribute to synapse dysfunction and memory impairment in AD. We found that T4 treatment significantly reduced cerebral Aβ deposits and lowered Aβ levels in brain homogenates. These effects coincided with a reduction in cleavage of β-carboxyl-terminal amyloid precursor protein (APP) fragment, levels of soluble APPβ, and protein expression of β-site APP cleaving enzyme 1. Taken together, our findings identify T4 as a potent negative regulator of brain Aβ levels and show that it significantly ameliorates synaptic degeneration and cognitive deficits in a mouse model of AD.
10.1111/jnc.13056
LRRK2 modulates microglial activity through regulation of chemokine (C-X3-C) receptor 1 -mediated signalling pathways.
Ma Bo,Xu Leyan,Pan Xiaodong,Sun Lixin,Ding Jinhui,Xie Chengsong,Koliatsos Vassilis E,Cai Huaibin
Human molecular genetics
Multiple missense mutations in Leucine-rich repeat kinase 2 (LRRK2) have been linked to Parkinson's disease (PD), the most common degenerative movement disorder. LRRK2 is expressed by both neurons and microglia, the residential immune cells in the brain. Increasing evidence supports a role of LRRK2 in modulating microglial activity, of which Lrrk2-null rodent microglia display less inflammatory response to endotoxin lipopolysaccharide (LPS). The underlying molecular mechanism, however, remains elusive. Chemokine (C-X3-C) receptor 1 (CX3CR1), predominantly expressed by microglia, suppresses microglial inflammation while promotes migration. Using whole-genome microarray screening, we found that Cx3cr1 mRNA levels were substantially higher in microglia derived from Lrrk2 knockout (Lrrk2) mice. The total and cell surface levels of CX3CR1 proteins were also remarkably increased. In correlation with the enhanced CX3CR1 expression, Lrrk2-null microglia migrated faster and travelled longer distance toward the source of fractalkine (CX3CL1), an endogenous ligand of CX3CR1. To investigate the impact of CX3CR1 elevation in vivo, we compared LPS-induced inflammation in the striatum of Lrrk2 knockout mice with Cx3cr1 heterozygous and homozygous knockout background. We found that a complete loss of Cx3cr1 restored the responsiveness of Lrrk2 microglia to LPS stimulation. In conclusion, our findings reveal a previously unknown regulatory role for LRRK2 in CX3CR1 signalling and suggest that an increase of CX3CR1 activity contributes to the attenuated inflammatory responses in Lrrk2-null microglia.
10.1093/hmg/ddw194
F-Labeled Benzyldiamine Derivatives as Novel Flexible Probes for Positron Emission Tomography of Cerebral β-Amyloid Plaques.
Li Zijing,Zhang Xuran,Zhang Xiaoyang,Cui Mengchao,Lu Jie,Pan Xiaodong,Zhang Xianzhong
Journal of medicinal chemistry
Early noninvasive visualization of cerebral β-amyloid (Aβ) plaques with positron emission tomography (PET) is the most feasible way to diagnose Alzheimer's disease (AD). In this study, a series of flexible benzyldiamine derivatives (BDA) were proposed for binding to aggregated β-amyloid 1-42 (Aβ) with high adaptability, high binding affinity (6.8 ± 0.6 nM), and rapid body excretion. The methylthio (12) and ethoxyl (10) derivatives were further labeled with F directly on their benzene ring and examined as PET probes for Aβ plaque imaging. [F]12 displayed 4.87 ± 0.52% ID/g initial uptake and prompt washout from normal brain in biodistribution studies. MicroPET-CT imaging indicated sufficient retention of [F]12 but lower white matter uptake in the brain of an AD transgenic mouse model compared with that of commercial [F]AV-45. Our experimental results provide new insights for developing targeting ligands possessing a flexible framework for use as efficient Aβ probes for PET imaging of AD brain.
10.1021/acs.jmedchem.6b01063
Netrin-1 Prevents Rat Primary Cortical Neurons from Apoptosis via the DCC/ERK Pathway.
Chen Jianhao,Du Houwei,Zhang Yixian,Chen Hongbin,Zheng Mouwei,Lin Peiqiang,Lan Quan,Yuan Qilin,Lai Yongxing,Pan Xiaodong,Chen Ronghua,Liu Nan
Frontiers in cellular neuroscience
In the nervous system, Netrin-1 serves as a neural guide, mediating the neuronal development. However, it remains blurred whether Netrin-1 can protect neurons from apoptosis induced by cerebral stroke. In the current study, the cultured rat primary cortical neurons were transfected with Netrin-1-encoding lentivirus before the oxygen-glucose-deprivation (OGD) treatment. Cell death and apoptosis were evaluated by lactate dehydrogenase (LDH) release and flow cytometry. We found that Netrin-1 attenuated OGD-induced cell death and neuronal apoptosis at 24 h after OGD treatment, and that the overexpression of Netrin-1 activated the ERK signaling pathway. These effects were partly abolished by blocking its receptor deleted in colorectal cancer (DCC) or U0126, an inhibitor of the ERK signaling pathway. Netrin-1 overexpression in neurons elevated the expression of DCC, on mRNA level and protein level. Netrin-1 also reduced DNA damage. Taken together, our findings suggest that Netrin-1 attenuates cell death and neuronal apoptosis via the DCC/ERK signaling pathway in the cultured primary cortical neurons after OGD injury, which may involve the mediation of DNA damage in the neurons.
10.3389/fncel.2017.00387
Netrin-1 Promotes Synaptic Formation and Axonal Regeneration via JNK1/c-Jun Pathway after the Middle Cerebral Artery Occlusion.
Zheng Mouwei,Chen Ronghua,Chen Hongbin,Zhang Yixian,Chen Jianhao,Lin Peiqiang,Lan Quan,Yuan Qilin,Lai Yongxing,Jiang Xinhong,Pan Xiaodong,Liu Nan
Frontiers in cellular neuroscience
As a secreted axon guidance molecule, Netrin-1 has been documented to be a neuroprotective factor, which can reduce infarct volume, promote angiogenesis and anti-apoptosis after stroke in rodents. However, its role in axonal regeneration and synaptic formation after cerebral ischemic injury, and the related underlying mechanisms remain blurred. In this study, we used Adeno-associated vectors carrying Netrin-1 gene (AAV-NT-1) to up-regulate the expression level of Netrin-1 in rats' brain after middle cerebral artery occlusion (MCAO). We found that the up-regulated level of Netrin-1 and its receptor DCC promoted axonal regeneration and synaptic formation; the overexpression of Netrin-1 activated the JNK1 signaling pathway; these effects were partially reduced when JNK1 signaling pathway was inhibited by SP600125 (JNK specific inhibitor). Taken together, these findings suggest that Netrin-1 can facilitate the synaptic formation and axonal regeneration via the JNK1 signaling pathway after cerebral ischemia, thus promoting the recovery of neural functions.
10.3389/fncel.2018.00013
Exenatide alleviates mitochondrial dysfunction and cognitive impairment in the 5×FAD mouse model of Alzheimer's disease.
An Jingjing,Zhou Yu,Zhang Mengjun,Xie Yunzhen,Ke Sujie,Liu Libin,Pan Xiaodong,Chen Zhou
Behavioural brain research
The role of mitochondrial dysfunction has been well-documented in Alzheimer's disease (AD). Glucagon-like peptide 1 (GLP-1) receptor agonists are being utilized as neuroprotectants in the treatment of various neurological disorders, including AD. We conducted this study to explore the effects of exenatide (a GLP-1 receptor agonist) on β-amyloid plaque (Aβ)-induced cognitive impairment and mitochondrial dysfunction in 5xFAD transgenic mice. Spatial memory test showed that exenatide administration (100 μg/kg twice per day) prevented cognitive decline after 16 weeks of treatment. Aβ deposition and synapse damage in the hippocampus was significantly alleviated. Furthermore, exenatide treatment can improve mitochondrial morphology, relieve oxidative damage, correct mitochondrial energy crisis, and normalize mitochondrial dynamics. These findings suggest that exenatide, which has already been applied in clinical medicine, may be a promising agent for AD therapy via mitochondrial protection.
10.1016/j.bbr.2019.111932
Restoration of L-OPA1 alleviates acute ischemic stroke injury in rats via inhibiting neuronal apoptosis and preserving mitochondrial function.
Redox biology
BACKGROUND:Ischemic stroke can induce changes in mitochondrial morphology and function. As a regulatory gene in mitochondria, optic atrophy 1 (OPA1) plays a pivotal role in the regulation of mitochondrial dynamics and other related functions. However, its roles in cerebral ischemia-related conditions are barely understood. METHODS:Cultured rat primary cortical neurons were respectively transfected with OPA1-v1ΔS1-encoding and OPA1-v1-encoding lentivirus before exposure to 2-h oxygen-glucose deprivation (OGD) and subsequent reoxygenation (OGD/R). Adult male SD rats received an intracranial injection of AAV-OPA1-v1ΔS1 and were subjected to 90 min of transient middle cerebral artery occlusion (tMCAO) followed by reperfusion. OPA1 expression and function were detected by in vitro and in vivo assays. RESULTS:OPA1 was excessively cleaved after cerebral ischemia/reperfusion injury, both in vitro and in vivo. Under OGD/R condition, compared with that of the LV-OPA1-v1-treated group, the expression of OPA1-v1ΔS1 efficiently restored L-OPA1 level and alleviated neuronal death and mitochondrial morphological damage. Meanwhile, the expression of OPA1-v1ΔS1 markedly improved cerebral ischemia/reperfusion-induced motor function damage, attenuated brain infarct volume, neuronal apoptosis, mitochondrial bioenergetics deficits, oxidative stress, and restored the morphology of mitochondrial cristae and mitochondrial length. It also preserved the mitochondrial integrity and reinforced the mtDNA content and expression of mitochondrial biogenesis factors in ischemic rats. INTERPRETATION:Our results demonstrate that the stabilization of L-OPA1 protects ischemic brains by reducing neuronal apoptosis and preserving mitochondrial function, suggesting its significance as a promising therapeutic target for stroke prevention and treatment.
10.1016/j.redox.2020.101503