共查询到20条相似文献,搜索用时 15 毫秒
1.
Eiki Takahashi Kimie Niimi Chitoshi Itakura 《Journal of molecular neuroscience : MN》2010,41(2):223-229
It has been reported earlier that interactions between Cav2.1α1 and calcium/calmodulin-dependent protein kinase II (CaMKII) in the presynaptic fraction and between the NMDA receptor subunit
NR2B and CaMKII in the postsynaptic density (PSD) fraction are important for neuronal function. Cav2.1α1, CaMKII, and NR2B are predominantly expressed in the hippocampus. To examine the above interactions and CaMKII activity in
the hippocampal presynapse and PSD of Rolling Nagoya mice carrying a mutation in Cav2.1α1 subunit, we performed immunoprecipitation and Western blot analyses. In the presynapse, the interaction between Cav2.1α1 and CaMKII and the phosphorylation of CaMKII (at Thr286) and its substrate Synapsin I (at Ser603) were decreased in mutant
mice compared to wild-type mice. In the PSD, a similar pattern was observed for the interaction between NR2B and CaMKII and
the phosphorylation of CaMKII (at Thr286) and its substrate AMPA receptor subunit glutamate receptor 1 (at Ser831) between
mutant and wild-type mice. Our data indicate that disruption of the interaction between Cav2.1α1 and CaMKII may down-regulate presynaptic CaMKII activity and that Rolling Nagoya mice would be a useful model for examining presynaptic function. 相似文献
2.
The changes in the mRNA levels of α2A and α2C adrenoceptors were investigated in unilateral 6-OHDA-lesioned rat model of Parkinson’s disease and l-DOPA-induced dyskinesia using in situ hybridization. In the untreated 6-OHDA-lesioned rats, α2A expression was elevated in the locus coeruleus (160 ± 8% and 142 ± 8% in lesioned and unlesioned sides compared to the comparable
side in sham-operated rats). Following long-term (21 days, twice daily) treatment with l-DOPA (25 mg/kg l-DOPA methyl ester plus benserazide 6.25 mg/kg) in 6-OHDA-lesioned rats, levels of α2A adrenoceptor mRNA in the locus coeruleus were decreased, compared to the 6-OHDA-lesioned rats, returning to the levels of
α2A mRNA in the sham-operated rats. α2A adrenoceptor expression was not changed in other brain regions in any treatment group. There was no change in α2C expression in the rostral or caudal striatum in which the highest density of α2C mRNA is present. In conclusion, the data presented in this study demonstrate an increase in α2A adrenoceptor mRNA in the locus coeruleus in the 6-OHDA-lesioned rat model of Parkinson’s disease. In addition, the data show
that repeated treatment with l-DOPA in 6-OHDA-lesioned rats, which induces dyskinesia, restores α2A mRNA levels. These changes of α2A mRNA expression, observed in the locus coeruleus, might be of importance to basal ganglia transmission and motor function. 相似文献
3.
Kazue?Kikuchi-Utsumi Mami?Ishizaka Nobuko?Matsumura Masahiko?Watabe Koji?Aoyama Nobuyuki?Sasakawa Toshio?Nakaki
Methamphetamine (METH) is a psychostimulant that damages nigrostriatal dopaminergic terminals, primarily by enhancing dopamine and glutamate release. α1-adrenergic receptor (AR) subtype involved in METH-induced neurotoxicity in rats was investigated using selective α1-AR antagonists. METH neurotoxicity was evaluated by (1) measuring body temperature; (2) determining tyrosine hydroxylase (TH) immunoreactivity levels; (3) examining levels of dopamine and its metabolites; and (4) assessing glial fibrillary acidic protein (GFAP) and microglial immunoreactivity in the striatum. METH caused a decrease in dopamine and TH levels and induced hyperthermia which is an exacerbating factor of METH neurotoxicity. Concurrently, METH increased GFAP expression and the number of activated microglia. Pretreatment with prazosin, a nonselective α1-AR antagonist, completely abolished METH-induced decrease in both dopamine and TH and caused a partial reduction in hyperthermia. Prazosin also prevented METH-induced increase in both GFAP expression and the number of activated microglia. In vivo microdialysis analysis revealed that prazosin, however, does not alter the METH-induced dopamine release in the striatum. The neuroprotective effects of prazosin could be mimicked by a selective α1D antagonist, BMY 7378, but not by selective α1A or α1B antagonists. These results suggest that the α1D-AR is involved in METH-induced hyperthermia and neurotoxicity in rats. 相似文献
4.
Arturo Reyes-Vaca Lizbeth de la Cruz Julieta Garduño Isabel Arenas David E. Garcia 《Journal of molecular neuroscience : MN》2017,63(3-4):377-384
Voltage-dependent regulation of CaV2.2 channels by G-proteins is performed by the β (Gβ) subunit. Most studies of regulation by G-proteins have focused on channel activation; however, little is known regarding channel inactivation. This study investigated inactivation of CaV2.2 channels in superior cervical ganglion neurons that overexpressed Gβ subunits. CaV2.2 currents were recorded by whole-cell patch clamping configuration. We found that the Gβ1 subunit reduced inactivation, while Gβ5 subunit did not alter at all inactivation kinetics compared to control recordings. CaV2.2 current decay in control neurons consisted of both fast and slow inactivation; however, Gβ1-overexpressing neurons displayed only the slow inactivation. Fast inactivation was restored by a strong depolarization of Gβ1-overexpressing neurons, therefore, through a voltage-dependent mechanism. The Gβ1 subunit shifted the voltage dependence of inactivation to more positive voltages and reduced the fraction of CaV2.2 channels resting in the inactivated state. These results support that the Gβ1 subunit inhibits the fast inactivation of CaV2.2 channels in SCG neurons. They explain the long-observed sustained Ca2+ current under G-protein modulation. 相似文献
5.
Franco R Lluis C Canela EI Mallol J Agnati L Casadó V Ciruela F Ferré S Fuxe K 《Journal of neural transmission (Vienna, Austria : 1996)》2007,114(1):93-104
Summary. The molecular basis for the known intramembrane receptor–receptor interactions among heptahelical receptors (G protein coupled
receptors, GPCR) was postulated to be heteromerization based on receptor subtype specific interactions between different types
of homomers of GPCR. Adenosine and dopamine receptors in the basal ganglia have been fundamental to demonstrate the existence
of receptor heteromers and the functional consequences of such molecular interactions. The heterodimer is only one type of
heteromeric complex and the evidence is equally compatible with the existence of higher order heteromeric complexes, where
also adapter proteins such as homer proteins and scaffolding proteins can exist, assisting in the process of linking the GPCR
and ion channel receptors together in a receptor mosaic that may have special integrative value and may constitute the molecular
basis for learning and memory. Heteromerization of D2 dopamine and A2A adenosine receptors is reviewed by Fuxe in another article in this special issue. Here, heteromerization between D1 dopamine and A1 adenosine receptors is reviewed. Heteromers formed by dopamine D1 and D2 receptors and by adenosine A1 and A2A receptors also occur in striatal cells and open new perspectives to understand why two receptors with apparently opposite
effects are expressed in the same neuron and in the nerve terminals. The role of accessory proteins also capable of interacting
with receptor–receptor heteromers in regulating the traffic and the molecular physiology of these receptors is also discussed.
Overall, the knowledge of the reason why such complex networks of receptor–receptor and receptor–protein interactions occur
in striatal cells is crucial to develop new strategies to combat neurological and neuropsychiatric diseases. 相似文献
6.
The effects of co-administration of either the dopamine precursor, L-Dopa, or the directly-acting, mixed dopamine (DA) agonist, apomorphine, with the alpha-adrenoceptor agonists, clonidine and guanfacine, upon the motor activity of hypoactive L-Dopa-tolerant MPTP-treated C57 BL/6 mice were measured in four experiments. In each case, MPTP (2 x 40 mg/kg, s.c., separated by a 24-hr interval) was administered eight-to-ten weeks before behavioural testing. It was found that clonidine co-administered with L-Dopa (20 mg/kg) restored motor activity in a dose- and parameter-related manner: locomotion and total activity were restored by the 1 mg/kg dose, rearing behaviour by the 0.3 and 1 mg/kg doses. The restorative effects of clonidine (1 mg/kg), co-administered with L-Dopa, were antagonised completely by pretreatment with yohimbine (1 mg/kg), but not by prazosin (1 mg/kg). Guanfacine (1 mg/kg) co-administered with L-Dopa (20 mg/kg) restored locomotor, but not rearing, behaviour in L-Dopa-tolerant MPTP-treated mice. The antikinesic action of guanfacine was antagonised completely by yohimbine (1 mg/kg), but not prazosin (1 mg/kg). Clonidine (1 or 3 mg/kg) co-administered with apomorphine (0.1, 0.3, 1.0 or 3.0 mg/kg), directly-acting DA agonist, did not restore motor behaviour in the hypokinesic L-Dopa-tolerant MPTP-treated mice. Nor did apomorphine, by itself, affect the motor activity of these animals. Neurochemical analysis indicated marked DA, DOPAC and HVA depletions in the striatum, and to a much lesser extent in the frontal cortex, of MPTP-treated mice. The synergistic antiparkinsonian action of clonidine with L-Dopa, but not apomorphine, in hypokinetic MPTP mice for the restoration of responding to a suprathreshold dose of L-Dopa, to which "wearing-off" had been induced previously, is discussed. 相似文献
7.
Different types of atherosclerotic (AS) lesions can be distinguished histologically and represent different stages of AS plaque development. Late-stage lesions more frequently develop complications such as plaque rupture and thrombosis with vessel occlusion than early AS lesions. To clarify whether protective, destructive, and inflammatory proteins are differentially expressed in early-stage and late-stage AS plaques we examined the proteinase inhibitor α2-macroglobulin (A2M), the neutrophil elastase (NE)—an enzyme degrading elastin and collagen fibers—and the proinflammatory protein interleukin-1α (IL-1α) in all types of AS plaques in the arteries of the circle of Willis from 78 human autopsy cases of both genders (61–91 years of age). Paraffin sections of AS plaques were immunostained with antibodies directed against A2M, NE and IL-1α. In initial AS lesions A2M was found, whereas NE and IL-1α were absent. NE and IL-1α became detectable as soon as a significant number of macrophages occurred within AS lesions. With increasing histopathological type of AS lesions, a marked increase of the area of the plaque exhibiting NE and IL-1α was observed. The area which exhibits A2M in AS plaques, on the other hand, did not vary significantly between the different stages. Thus, our results indicate a disproportionately high increase of the destructive enzyme NE and the proinflammatory protein IL-1α in relation to A2M with the progression of the grade of AS lesions pointing to the transgression of the protective capacity of A2M by NE and IL-1α in late-stage plaques. Therefore, our findings support the hypothesis that NE-induced tissue damage in late-stage AS plaques contributes to the development of plaque rupture and subsequent thrombosis. 相似文献
8.
Přikrylová Vranová H Mareš J Hluštík P Nevrlý M Stejskal D Zapletalová J Obereigneru R Kaňovský P 《Journal of neural transmission (Vienna, Austria : 1996)》2012,119(3):353-362
Parkinson’s disease (PD) is a neurodegenerative disorder with highly heterogeneous clinical manifestations. This fact has
prompted many attempts to divide PD patients into clinical subgroups. This could lead to a better recognition of pathogenesis,
improving targeted treatment and the prognosis of PD patients. The aim of the present study was to obtain cerebrospinal fluid
(CSF) samples in PD patients and to search for a relationship between neurodegenerative CSF markers (tau protein, beta-amyloid1-42 and index tau protein/beta-amyloid1-42) and the clinical subtypes. PD patients were divided into three subgroups: early disease onset (EDO), tremor-dominant PD
(TD-PD), and non-tremor dominant PD (NT-PD) according to the previously published classification. Neurodegenerative markers
in the CSF were assessed in these three groups of patients suffering from PD (EDO-17, TD-15, NT-16 patients) and in a control
group (CG) of 19 patients suffering from non-degenerative neurological diseases and 18 patients with Alzheimer’s disease (AD).
The NT-PD patients were found to have significantly higher levels of CSF tau protein and index tau/beta than the control subjects
and other Parkinsonian subgroups, but no significant differences in these markers were found between AD and NT-PD patients.
In the context of more rapid clinical progression and more pronounced neuropathological changes in the NT-PD patient group,
our results corroborate the opinion that CSF level of tau protein may be regarded as a potential laboratory marker of the
presence and severity of neurodegeneration. 相似文献
9.
Background Obstructive vascular lesions at the terminal portion of the internal carotid arteries are thought to be the primary and essential lesions in moyamoya disease. The etiology remains unknown. To detect possible mediators of the thickened intima of moyamoya disease, we measured serum alpha-1-antitrypsin (1-AT) levels and characterized the phenotype of patients with familial moyamoya disease.Patients and methods Fifty-six individuals were examined, including 29 patients with moyamoya disease from 14 families. Serum 1-AT levels were analyzed by electroimmunoassay and genomic phenotype by isoelectric focusing.Results All individuals had a normal 1-AT phenotype. The average serum 1-AT level in moyamoya disease patients was significantly higher than that of normal individuals, although both were within the normal range.Conclusions These findings suggest that serum 1-AT level may be a marker, rather than an etiologic factor, indicating the progression of moyamoya disease. 相似文献
10.
11.
Qinggan Zeng Rongyong Man Yifeng Luo Ling Zeng Yushi Zhong Bingxun Lu Xiaofeng Wang 《Journal of molecular neuroscience : MN》2017,61(2):159-168
Using microarray analysis, we detected microRNA-124 (miR-124) to be abundantly expressed in the olfactory bulb (OB). miR-124 regulates adult neurogenesis in the subventricular zone (SVZ). However, much less is known about its role in newborn OB neurons. Here, using both gain-of-function and loss-of-function approaches, we demonstrate that brain-specific miR-124 affects dendritic morphogenesis and spine density in newborn OB neurons. Functional Annotation Clustering of miR-124 targets was enriched in “cell morphogenesis involved in neuron differentiation.” 相似文献
12.
Platelet phospholipase A<Subscript>2</Subscript> activity in Alzheimer’s disease and mild cognitive impairment 总被引:1,自引:0,他引:1
Gattaz WF Forlenza OV Talib LL Barbosa NR Bottino CM 《Journal of neural transmission (Vienna, Austria : 1996)》2004,111(5):591-601
Summary. Phospholipase A2 (PLA2) controls the metabolism of phospholipids in cell membranes. In the brain, PLA2 influences the processing of the amyloid precursor protein (APP) and thus the production of the amyloid-beta peptides (A), which are the major components of the senile plaques in Alzheimers disease (AD). Reduced PLA2 activity has been reported in brain and in platelets of AD patients. In the present study we investigated PLA2 activity in platelets from 21 AD patients as compared to 17 healthy elderly controls and 11 individuals with mild cognitive impairment (MCI). Subjects were cognitively assessed by the Mini-Mental State Examination (MMSE) and the CAMDEX schedule. Platelet PLA2 activity was determined by radio-enzymatic assay, which mainly detected a calcium-independent form of the enzyme present also in the brain (iPLA2). PLA2 activity was significantly lower in AD than in controls (p<0.001). Mean PLA2 activity in MCI individuals was between the values of AD patients and controls, with a subgroup showing PLA as low as the lowest AD patients, but the differences from MCI were not significant from AD and control groups. Lower PLA2 activity was significantly correlated with a worse cognitive performance both at the MMSE (p=0.001) and the cognitive sub-scale of the CAMDEX inventory (p=0.002). Our data replicate previous findings of reduced platelet PLA2 activity in AD. Both reduced PLA2 activity and the correlation with impaired cognition were also reported in brain tissue of AD patients, suggesting thus that the present determinations in platelets may be related to a reduction in the brain. In the brain the inhibition of PLA2 inhibits the physiological secretion of the APP, a mechanism that increases A formation. Further longitudinal studies should investigate whether those MCI individuals with the lowest PLA2 values in platelets would be at a higher risk to develop AD during a longitudinal follow up. 相似文献
13.
Xue Fu Meiling Ke Weihua Yu Xia Wang Qian Xiao Min Gu Yang Lü 《Journal of molecular neuroscience : MN》2018,65(2):179-189
Inhibition of endocytosis in an Alzheimer’s disease (AD) model has been shown to be able to prevent amyloid β (Aβ)-induced damage and to exert a beneficial effect in treating AD. Adaptor-associated kinase 1 (AAK1), which binds to the adaptor protein complex 2 (AP-2), regulates the process of clathrin-mediated endocytosis. However, how AAK1 expression varies over the course of AD is unknown. In this study, we investigated AAK1 levels in AD model mice over time. Aβ1–42 was used to establish a mouse AD model, and the Morris water maze test was used to characterize the time course of Aβ1–42-induced cognition changes. ELISA was used to determine AAK1 levels in plasma and Aβ1–42 levels in brain tissues. Subsequently, the protein or gene levels of AAK1, AP-2, and Rab5 (an early endosome marker) were tested in each group. The cognitive function of Aβ1–42-induced mice was significantly declined compared to control group, and the deficits reached a peak on day 14, but partly recovered on day 30. Moreover, the level of Aβ1–42 detected with ELISA was highest on day 14, but reduced on day 30, paralleling the cognitive changes in the mice in our study. AAK1, AP-2, and Rab5 expression showed the same periodic variation as the changes in cognition. Thus, periodic variation in AAK1 expression is closely correlated to the decline in cognition, and AAK1 might be a suitable indicator for Alzheimer’s disease. 相似文献
14.
Forlenza OV Schaeffer EL Gattaz WF 《Journal of neural transmission (Vienna, Austria : 1996)》2007,114(2):231-238
Summary. Phospholipase A2 (PLA2) is a key enzyme in cerebral phospholipid metabolism. Preliminary post-mortem studies have shown that PLA2 activity is decreased in frontal and parietal areas of the AD brain, which is in accordance with recent 31P-Magnetic Resonance Spectroscopy evidence of reduced phospholipid turnover in the pre-frontal cortex of moderately demented
AD patients. Such abnormality may also be observed in peripheral cells, and reduced PLA2 activity in platelet membranes of AD patients, and correlates with the severity of dementia. In rat hippocampal slices, PLA2 has been implicated in mechanisms of synaptic plasticity. In adult rats, the stereotaxic injection of PLA2 inhibitors in the CA1 area of hippocampus impaired, in a dose-dependent manner, the formation of short- and long-term memory.
Additionally, such inhibition resulted in a reduction of the fluidity of hippocampal membranes. In primary cultures of cortical
and hippocampal neurons, the inhibition of PLA2 precluded neurite outgrowth, and the sustained inhibition of the enzyme in mature cultures lead to loss of viability. Taken
together, these findings reinforce the involvement of PLA2 enzymes in neurodevelopment and neurodegeneration processes, and further suggest that reduced PLA2 activity, probably reducing membrane phospholipids breakdown, may contribute to the memory impairment in AD. 相似文献
15.
ProThyrotropin-releasing hormone (proTRH) is a prohormone widely distributed in many areas of the brain. After biosynthesis,
proTRH is subjected to post-translational processing to generate TRH and seven non-TRH peptides. Among these non-TRH sequences,
we found previously that preproTRH178–199 could regulate the secretion of prolactin in suckled rats by their pups. Dopamine (DA), the main regulator of prolactin secretion,
is produced in dopaminergic tyrosine hydroxylase (TH)-positive neurons in the hypothalamic arcuate nucleus (ARC). In this
study we investigated whether prolactin release during the estrous sexual cycle is regulated by prepro TRH178–199 through its effecton DA neurons of the ARC. We observed that biotinylated prepro TRH178–199 bound to neurons in the ARC; this was higher during proestrus than during diestrus. Binding of preproTRH178–199 to DA neurons was seen only during proestrus in the ARC. Using primary neuronal hypothalamic cultures we found that preproTRH178–199peptide decreased TH levels in a dose-responsive manner, whereas intra-ARC administration of preproTRH178–199 induced a 20-fold increase in plasma prolactin levels. Together, these results suggest a potential role for preproTRH178–199 in regulating dopaminergic neurons involved in the inhibition of pituitary prolactin release. 相似文献
16.
Many currently prescribed antiepileptic drugs (AEDs) act via voltage-gated sodium channels, through effects on γ-aminobutyric
acid-mediated inhibition, or via voltage-gated calcium channels. Some newer AEDs do not act via these traditional mechanisms.
The molecular targets for several of these nontraditional AEDs have been defined using cellular electrophysiology and molecular
approaches. Here, we describe three of these targets: α2δ, auxiliary subunits of voltage-gated calcium channels through which the gabapentinoids gabapentin and pregabalin exert their
anticonvulsant and analgesic actions; SV2A, a ubiquitous synaptic vesicle glycoprotein that may prepare vesicles for fusion
and serves as the target for levetiracetam and its analog brivaracetam (which is currently in late-stage clinical development);
and Kv7/KCNQ/M potassium channels that mediate the M-current, which acts a brake on repetitive firing and burst generation and serves
as the target for the investigational AEDs retigabine and ICA-105665. Functionally, all of the new targets modulate neurotransmitter
output at synapses, focusing attention on presynaptic terminals as critical sites of action for AEDs. 相似文献
17.
The purpose of the study was to determine whether Aβ1–42 and p-Tau181 cerebral spinal fluid (CSF) levels can predict progression from amnestic mild cognitive impairment (aMCI) to Alzheimer’s disease dementia (ADD) in a 3-year follow-up study. All participants were evaluated blindly by a behavioral neurologist and a neuropsychologist, and classified according to the Petersen criteria for aMCI and according to the Clinical Dementia Rating (CDR) scale. Individuals were also submitted to lumbar puncture at baseline. Levels of Aβ1–42 and p-Tau181 were measured by immunoenzymatic assay. Values were adjusted for age and sex. Thirty-one of 33 (93.9%) participants completed follow-up. Approximately 39% of aMCI individuals progressed to ADD. The relative risk of developing ADD in those with Aβ1–42 CSF levels lower than 618.5 pg/mL was 17.4 times higher than in those whose levels were higher than 618.5 pg/mL (P?=?0.003). p-Tau181 alone did not predict progression to ADD (P?=?0.101). The relative risk in those with a p-Tau181/Aβ1–42 ratio higher than 0.135 was 5.7 times greater (P?<?0.001). Aβ1–42 and p-Tau181 explained 40.1% of the verbal memory test subscore of the Consortium to Establish a Registry for Alzheimer’s Disease (ΔCERADs) variance (P?=?0.008). Aβ1–42 strongly predicted progression from aMCI to ADD. p-Tau181 alone, or its relation to Aβ1–42, was inferior than Aβ1–42 alone as a predictor of progression to ADD. 相似文献
18.
Prolonged spin–spin relaxation times in tumour tissue have been observed since some of the earliest nuclear magnetic resonance investigations of the brain. Over the last three decades, numerous studies have sought to characterize tumour morphology and malignancy using quantitative assessment of T 2 relaxation times, although attempts to categorize and differentiate tumours have had limited success. However, previous work must be interpreted with caution as relaxation data were typically acquired using a variety of multiple echo sequences with a range of echoes and T 2 decay curves and were frequently fit with monoexponential analysis. We defined the distribution of T 2 components in three different human brain tumours (glioblastoma, oligodendroglioma, meningioma) using a multi-echo sequence with a greater number of echoes and a longer acquisition window than previously used (48 echoes, data collection out to 1120 ms) with no a priori assumptions about the number of exponential components contributing to the T 2 decay. T 2 relaxation times were increased in tumour tissue and each tumour showed a distinct T 2 distribution profile. Tumours have complex and unique compartmentalization characteristics. Quantitative assessment of T 2 relaxation in brain cancer may be useful in evaluating different grades of brain tumours on the basis of their T 2 distribution profile, and has the potential to be a non-invasive diagnostic tool which may also be useful in monitoring therapy. Further study with a larger sample size and varying grades of tumours is warranted. 相似文献
19.
Krzystanek E Krzystanek M Opala G Trzeciak HI Siuda J Małecki A 《Journal of neural transmission (Vienna, Austria : 1996)》2007,114(8):1033-1039
Summary Phospholipase A2 (E.C. 3.1.1.4, PLA2) plays an essential role in metabolism of membrane phospholipids, it is related to inflammatory reactions, secretion of amyloid
precursor protein and activation of NMDA receptor after ischemia.
In the present study we investigated PLA2 activity in platelets from 37 Alzheimer’s disease (AD) patients, 32 vascular dementia (VaD) patients and 32 individuals with
ischemic stroke as compared to 27 healthy elderly controls. PLA2 activity was determined using radiometric assay.
Mean platelet PLA2 activity was increased in individuals with Alzheimer’s disease (p < 0.001). In VaD group the enzyme activity was between the values in AD and controls, these differences being significant
from both groups. In the group of patients with ischemic stroke mean PLA2 activity was higher either 48 h after the stroke or 7 days later (in both cases p < 0.001).
The results may be particularly interesting in light of the fact, that inhibitors of PLA2 activity are known. 相似文献
20.
Daniel K. Y. Chan Nady Braidy Ying Hua Xu Tim Chataway Feng Guo Gilles J. Guillemin Charlie Teo Wei Ping Gai 《Neurotoxicity research》2016,30(3):479-485
Increasing evidence suggests an important role of alpha-synuclein (α-Syn) in the pathogenesis of Parkinson’s disease (PD). The inter-neuronal spread of α-Syn via exocytosis and endocytosis has been proposed as an explanation for the neuropathological findings of PD in sub-clinical and clinical phases. Therefore, interfering the uptake of α-Syn by neurons may be an important step in slowing or modifying the propagation of the disease. The purposes of our study were to investigate if the uptake of α-Syn fibrils can be specifically interfered with monomeric β-Amyloid1–40 (Aβ40) and to characterise the core acting site of interference. Using a radioisotope-labelled uptake assay, we found an 80 % uptake reduction of α-Syn fibrils in neurons interfered with monomeric Aβ40, but not β-Amyloid1–42 (Aβ42) as compared to controls. This finding was further confirmed by enzyme-linked immunosorbent assay (ELISA) with α-Syn uptake reduced from about 80 % (Aβ42) to about 20 % (Aβ40) relative to controls. To define the region of Aβ40 peptide capable of the interference, we explored shorter peptides with less amino acid residues from both the C-terminus and N-terminus. We found that the interference effect was preserved if amino acid residue was trimmed to position 11 (from N-terminus) and 36 (from C-terminus), but dropped off significantly if residues were trimmed beyond these positions. We therefore deduced that the “core acting site” lies between amino acid residue positions 12–36. These findings suggest α-Syn uptake can be interfered with monomeric Aβ40 and that the core acting site of interference might lie between amino acid residue positions 12–36. 相似文献