Exploring the vital role of microglial membrane receptors in Alzheimer’s disease pathogenesis: a comprehensive review

Neurodegenerative diseases constitute a broad category of diseases caused by the degeneration of the neurons.They are mainly manifested by the gradual loss of neuron structure and function and eventually can cause death or loss of neurons.As the global population ages rapidly,increased people are being diagnosed with neurodegenerative diseases.It has been established that the onset of Alzheimer’s disease(AD)is closely linked with increasing age and its major pathological features include amyloid-beta plaques(Aβ),Tau hyperphosphorylation,Neurofibrillary tangles(NFTs),neuronal death as well as synaptic loss.The involvement of microglia is crucial in the pathogenesis and progression of AD and exhibits a dual role.For instance,in the early stage of AD,microglia surface membrane proteins or receptors can participate in immunophagocytosis,and anti-inflammatory functions and act as a physical barrier after recognizing various ligands such as Aβand NFTs.However,in the later stage of the disease,membrane receptors on the surface of microglia can cause its activation to release a substantial quantity of pro-inflammatory factors.Which can amplify the neuroinflammatory response.The rapid decline of normal immune phagocytosis can result in the continuous accumulation of abnormal proteins,leading to neuronal dysfunction and destruction of the formed physical barrier as well as the neurovascular microenvironment.It can also increase the transformation of microglia from anti-inflammatory phenotype M2 to pro-inflammatory phenotype M1,induce severe neuronal injury or apoptosis,and aggravate the progression of AD.Due to few articles have focused on the AD-related membrane protein receptors on microglia,thus in this paper,we have reviewed several representative microglial membrane proteins or receptors about their specific roles and functions implicated in AD,and expect that there will be more in-depth research and scientific research results in the treatment of AD by targeted regulation of microglia membrane protein receptors in the future.

Soluble p75 neurotrophic receptor as a reliable biomarker in neurodegenerative diseases: what is the evidence?

Neurodegenerative diseases are often misdiagnosed,especially when the diagnosis is based solely on clinical symptoms.The p75 neurotrophic receptor(p75^(NTR))has been studied as an index of sensory and motor nerve development and maturation.Its cleavable extracellular domain(ECD)is readily detectable in various biological fluids including plasma,serum and urine.There is evidence for increased p75NTR ECD levels in neurodegenerative diseases such as Alzheimer’s disease,amyotrophic lateral sclerosis,age-related dementia,schizophrenia,and diabetic neuropathy.Whether p75^(NTR) ECD could be used as a biomarker for diagnosis and/or prognosis in these disorders,and whether it could potentially lead to the development of targeted therapies,remains an open question.In this review,we present and discuss published studies that have evaluated the relevance of this emerging biomarker in the context of various neurodegenerative diseases.We also highlight areas that require further investigation to better understand the role of p75^(NTR) ECD in the clinical diagnosis and management of neurodegenerative disorders.

Cortico-striatal gamma oscillations are modulated by dopamine D3 receptors in dyskinetic rats

Long-term levodopa administration can lead to the development of levodopa-induced dyskinesia.Gamma oscillations are a widely recognized hallmark of abnormal neural electrical activity in levodopa-induced dyskinesia.Currently,studies have reported increased oscillation power in cases of levodopa-induced dyskinesia.However,little is known about how the other electrophysiological parameters of gamma oscillations are altered in levodopa-induced dyskinesia.Furthermore,the role of the dopamine D3 receptor,which is implicated in levodopa-induced dyskinesia,in movement disorder-related changes in neural oscillations is unclear.We found that the cortico-striatal functional connectivity of beta oscillations was enhanced in a model of Parkinson’s disease.Furthermore,levodopa application enhanced cortical gamma oscillations in cortico-striatal projections and cortical gamma aperiodic components,as well as bidirectional primary motor cortex(M1)↔dorsolateral striatum gamma flow.Administration of PD128907(a selective dopamine D3 receptor agonist)induced dyskinesia and excessive gamma oscillations with a bidirectional M1↔dorsolateral striatum flow.However,administration of PG01037(a selective dopamine D3 receptor antagonist)attenuated dyskinesia,suppressed gamma oscillations and cortical gamma aperiodic components,and decreased gamma causality in the M1→dorsolateral striatum direction.These findings suggest that the dopamine D3 receptor plays a role in dyskinesia-related oscillatory activity,and that it has potential as a therapeutic target for levodopa-induced dyskinesia.

Progesterone receptor membrane component 1 as a potential prognostic biomarker for hepatocellular carcinoma

AIM To investigate the clinicopathological significance of progesterone receptor membrane component 1(PGRMC1) and PGRMC2 in hepatocellular carcinoma(HCC). METHODS We performed immunohistochemical staining to evaluate the estrogen receptor(ER), progesterone receptor(PR), PGRMC1, and PGRMC2 in a clinical cohort consisting of 89 paired HCC and non-tumor liver samples. We also analyzed HCC data(n = 373) from The Cancer Genome Atlas(TCGA). We correlated the expression status of PGRMC1 and PGRMC2 with clinicopathological indicators and the clinical outcomes of the HCC patients. We knocked down or overexpressed PGRMC1 in HCC cell lines to evaluate its biological significance in HCC cell proliferation, differentiation, migration, and invasion. RESULTS We found that few HCC cases expressed ER(5.6%) and PR(4.5%). In contrast, most HCC cases expressed PGRMC1(89.9%) and PGRMC2(100%). PGRMC1 and PGRMC2 exhibited significantly lower expression in tumor tissue than in non-tumor tissue(P < 0.001). Lower PGRMC1 expression in HCC was significantly associated with higher serum alpha-fetoprotein expression(P = 0.004), poorer tumor differentiation(P = 0.045) and liver capsule penetration(P = 0.038). Low PGRMC1 expression was an independent predictor for worse disease-free survival(P = 0.002, HR = 2.384,CI: 1.377-4.128) in our cases, as well as in the TCGA cohort(P < 0.001, HR = 2.857, CI: 1.781-4.584). The expression of PGRMC2 did not relate to patient outcome. PGRMC1 knockdown promoted a poorly differentiated phenotype and proliferation of HCC cells in vitro, while PGRMC1 overexpression caused the opposite effects.CONCLUSION PGRMC1 is a non-classical hormonal receptor that negatively regulates hepatocarcinogenesis. PGRMC1 down-regulation is associated with progression of HCC and is a poor prognostic indicator.

The Effect of GnRHa Induced Superovulation on Endometrial Morphology and Estrogen Receptor and Progesterone Receptor in Mouse

To evaluate the effect of GnRHa induced superovulation protocol on endometrial morphology and function. Material & Methods Forty ICR mice were randomly allocated into 4 groups, among them, 2 experimental groups were injected with GnRHa+HMG+hCG, another 2 groups were given saline of same volume as control group. The uterine tissues were investigated at 24 h and 48 h after administration (experimental group) or ovulation (control group).The endometrial thickness, the size of gland and glandular lumen, the total area of glandular cells, the average height of glandular epithelium were measured from routine histological slides using computerized image analysis. The SP immunohistochemistry techniques with monoclonal antibodies were employed to semi quantitatively analize the estrogen receptor (ER) and progesterone receptor (PR) in glandular cells. Results The endometrial thickness was not significantly different between experimental groups and control groups at 24 h and 48 h (P>0.05).The average area, perimeter, maximal diameter of single gland and glandular lumen, the total area, average height of glandular epithelium in experimental groups were significantly smaller than those of in control groups at equivalent time stages (all P<0.01). The asynchronous development of gland epithelium and stroma cells, namely, pesudostratified glandular epithelium and predecidual changes of stroma cells were seen at same time in experimental groups. The positive percentage (%) and expression intense of ER and PR in glandular epithelium cells were significantly lower in experimental groups than in control groups (P<0.05). Conclusion The protocol with GnRHa had a negative effect on endometrial histological structure and down regulated the express of ER and PR, suggesting that this protocol effect on the endometrial morphology and function and could not facilitate the formation of a physiologic endometrium completely, which may be one of the causes of low pregnancy rates.

Progesterone effects on the oligodendrocyte linage: all roads lead to the progesterone receptor

A new role has emerged for progesterone after discovering its potent actions away from reproduction in both the central and the peripheral nervous system. The aim of the present report is to discuss progesterone’s mechanisms of action involved in myelination, remyelination and neuroinflammation. The pivotal role of the classic progesterone receptor is described and evidence is compiled about progesterone’s direct effects on oligodendrocyte linage and its indirect effects on oligodendrocyte precursor cell differentiation by decreasing the neuroinflammatory environment.

Effects of coriaria lactone-activated,astrocyte-conditioned medium on estrogen receptor and progesterone receptor expression in rat cortical and hippocampal neurons

BACKGROUND： Coriaria lactone-activated astrocytes released bioactive substances that eventually caused epilepsy. OBJECTIVE： It has been suggested that activated astrocytes alter the expression of the estrogen receptor and progesterone receptor by releasing bioactive substances during epilepsy, thereby affecting neuronal activity in the brain. This study was designed to observe the expression of the estrogen receptor and the progesterone receptor in rat brain following lateral ventricle injection of coriaria lactone-activated, astrocyte-conditioned medium. DESIGN AND SETTING： This immunohistochemical, randomized, controlled, animal study was conducted at the Department of Pathology, Hospital Affiliated to Binzhou Medical College, China. MATERIAL： Coriaria lactone was provided by Huaxi Pharmaceutical Factory, China. METHODS： Forty adult, healthy, male, Sprague Dawley rats were randomly assigned into two groups. Astrocyte-conditioned medium （10 μ L） was injected into rat lateral ventricle in the control group （n = 8）. Coriaria lactone-activated, astrocyte-conditioned medium （10 μL） was infused into the rat lateral ventricle in the coriaria lactone group （n = 32）. At 2, 4, 8 and 12 hours following injection, rats were sacrificed and subjected to immunohistochemistry. Eight rats were studied at each time point. MAIN OUTCOME MEASURES： Behavioral changes were observed in rats of both groups. Expression of the estrogen receptor and the progesterone receptor in rat cortical and hippocampal neurons was measured using immunohistochemistry. RESULTS： Four hours after injection, estrogen receptor levels in rat cortical and hippocampal neurons were significantly higher in the coriaria lactone group than in the control group （P 〈 0.05）. Progesterone receptor levels were significantly lower in the coriaria lactone group than in the control group （P 〈 0.05）. Seizures were not observed in the control group. In the coriaria lactone group, convulsions appeared 30 minutes after injection; seizures reached grade Ⅲ at 45 minutes rat behavior was nearly normal at 2 hours. CONCLUSION： Activated astrocytes can induce seizures in the rat by enhancing estrogen receptor expression and decreasing progesterone receptor expression in cerebral cortical and hippocampal neurons.

IMMUNOHISTOCHEMICAL STUDY OF ESTROGEN AND PROGESTERONE RECEPTOR IN THYROID TISSUES OF AUTOIMMUNE THYROID DISEASE

Estrogen receptor(ER) and progesterone receptor (PgR) in core-needle biopsied thyroidtissues of 30 cases of autoimmune thyroid disease and 2 cases of simple gotter were measured usingenzyme-linked histochemical technique. The results showed that the frequences of presence of ER inGraves' disease (GD) and Hashimoto's thyroditis(HT) were 50% (9/18) and 58. 3K (7/12) respectively ; and those of PgR were 11. 1 % (2/18) in GD, 16. 2% (2/7) in HT. Both ER and PgR werenegative in simple gotter. This study demonstrated that the content of ER in thyroid tissues of autoimmune thyroid disease was relatively high, suggesting that estrogen may play a role in the development of the disease.

Similarity between Spatial-temporal Expression Patterning of HOXAll and Progesterone Receptor in Human Endometrium

Objective To study HOXAll expression and its correlation with that of the progesterone receptor (PR) gene in human endometriumMethods In situ hybridization and semi-quantitative RT-PCR were used. Results HOXAll mRNA was detected in both stromal and glandular cells of normal endometrium by in situ hybridization. But the expression levels in the glandular cells had a dramatic decline or even disappearance at mid-secretory stage. Semi-quantitative RT-PCR analysis, however, demonstrated that the total expression levels of HOXAll mRNA were markedly increased in the mid-secretory endometrium, which suggested that there was an increased expression in stromal cells. Similar results were obtained for PR gene expression in human endometrium by in situ hybridization and semi-quantitative RT-PCR analysis.Conclusion HOXAll gene spatial and temporal expression patterns were similar to that of PR gene in endometrium across menstrual cycle, and HOXAll was closely related to the endometrial proliferation and differentiation during menstrual cycle, especially the establishment of receptive status in implantation.

Selective Expression of Progesterone Receptor in Malignant Melanoma Was Inversely Correlated with PCNA

To investigate the role of progesterone receptor （PR） expression in malignant melanoma （MM）, PR and proliferative cell nuclear antigen （PCNA） expression were immunohistochemistrically evaluated in a series of 35 specimens of MM, and the correlation between the immunohistochemistrical findings and clinicopathological data was also analyzed. PR expression was detected in 25.7% （9/35） of the patients with MM. No PR expression was observed in nevi. PR expression was inversely correlated with PCNA expression （r=-0.353, P=-0.026）. PR expression was slightly increased in females, subjects aged under 55 y, those with ulceration, non-acral subtype and diagnosis delay longer than 1 y, but the difference was not statistically significant. Selective expression of progesterone receptor in malignant melanoma might be correlated with inhibited tumor growth.

Neurofibromatosis type 2 gene mutation and progesterone receptor messenger RNA expression in the pathogenesis of sporadic orbitocranial meningioma

AIM: To investigate neurofibromatosis type 2(NF2) gene mutation at mRNA levels in sporadic orbitocranial meningioma and its association with progesterone receptor(PR) mR NA expression.METHODS: This was a case-control study. Thirty-four sporadic meningioma patients with no familial NF2-related meningioma history were recruited. They were interviewed for their obstetric, gynecologic, and contraception history. PR investigation was performed with real-time polymerase chain reaction(PCR). NF2 mutation was investigated using Qbiomarker Somatic Mutation PCR Assay at NF2 mRNA level after its cDNA extraction(four mRNA mutation cytoband coordinates for nucleotide change: c.634 C>T/p.Q212, c.655 G>A/p.V219 M, c.784 C>T/p.R262 and c.1228 C>T/p. Q410). RESULTS: After mutation analysis at mRNA level, NF2 gene mutation was found in 35.29% patients. Non-mutation group was strongly associated with exogenous hormonal exposure(non-mutation vs mutation: 95.5% vs 83.3%, P<0.001). PR mR NA was found significantly lower in nonmutation group(P=0.033) which presumed as long term exogenous progesterone exposure. However, mutation group was associated with higher rate of progression to gradeⅡ(mutation vs non-mutation, 18.2% vs 5%, P<0.001) and was associated more in fibrous and anaplastic tumor tissue.CONCLUSION: NF2 mutation-meningioma is associated with higher grade of meningioma. Non NF2 mutationmeningioma is strongly associated with exogenous progesterone exposure and lower PR expression.

Effects of Mifepristone Compound on the Receptors of Estrogen and Progesterone in Early Pregnancy Deciduas

To examine the effect of mifepristone compound (mifepristone + anor- drin) on estrogen receptor (ER) and progesterone receptor (PR) in early pregnancy decidua. Materials & Methods A Controlled study was carried out among 60 normal early pregnant volunteers (≤49d) in the department of obstetric and gynecology of Peking Union Medical Hospital. The concentrations of ER and PR were measured by radio- ligand and were compared with the control subjects after oral administration of mifepristone or mifepristone compound in different doses. Results The concentration of PR decreased while that of ER increased significantly in the decidua from all subjects administrated with mifepristone compound. We also found the concentration of EcR in Group 5 (mifepristone 30 mg + AF-53 5 mg) was the highest among 6 groups. The compound may be in favor of estrogen's action on endometrium. Conclusion The results indicate that mifepristone compound with AF- 53 has a coordi- nated function and can change the proportion of PR and ER. Hence, it can facilitate abortion. The compound dose of mifepristone 30 mg + AF-53 5mg is in favor of the endometrium recovering.

Clinical Significance of Estrogen and Progesterone Receptors Assays in Pancreatic Carcinoma

Cyochemical methods for demonstrating estrogen receptor (ER) and progesterone receptor (PgR)within pancreas-cancer cells showed positive reation of ER or/and PgR in 4 out of 8 pancreatic carcinomas.This result suggested that sex hormone might be closely linked to pancreatic cancer.Pancreatic carcinoma could be considered a hormoneresponsive-neoplasm. The hormone migh be a cause influencing the growth of pancreatic carcinoma in association with receptors described. Endocrine therapy would be a treatment of choice for pancreatic carcinoma.

STUDY OF ESTROGEN RECEPTOR AND PROGESTERONE RECEPTOR IN SQUAMOUS CELL CARCINOMA TISSUE OF ORAL MUCOSA

By means of the enzyme linked affinity histothemical method, 45 cases of squamous cell carcinoma(SCC) of the oral mucosa and 15 cases of the approximately normal oral mucosal tissue were detected for estrogen receptor(ER) and progesterone receptor(PR). The results indicated that In the SCC tissue of the oral mucosa there were 5 cases of ER+ and PR- and 32 cases of both ER+ and PR+. Thirty-seven cases, the summation of the above two items, were considered as receptor(+),therefore the rate of the receptor(+) being 82.22%. ER+ and PR+ were cd related to the sex and age of patients, the neck lymph nodes' metastasizing or not and affected parts of the tumor, while they were related to the differentiation degree of the tumor. The rate of receptor(+) decreased with the decrease of the differentiation degree of the tumor. By X2 test a remarkable difference between grade Ⅰand grade Ⅲ of SCC of the oral mucosa was shown. It is suggested that SCC of the oral mucosa may probobly be hormone dependent tumor. The authors consider that the SCC detection for ER and PR could not only be one of the indices of biologic characteristics for that tumor but also as bases of anti-hormone treatment.

Expression of Progesterone and Estrogen Receptors in Human Renal Cell Carcinoma

Progesterone receptor(PR) and estrogen receptor(ER) were investigated in 29 specimens of renal cell carcinoma (RCC) and its autologous kidneys, 12 samples of control kidnerys with high sensitive and specific enzymelabelled histochemical techniques. The positive expression rates of PR in RCC, its autologous kidneys and control kidneys were 31.0%, 82.8% and 83.3% respectively, while the positive expression rates of ER of those tissues were 58.6%, 79.3% and 83.3%, respectively. It showed that the positive rate and the value of PR and ER in RCC were significantly less than those determined in the autologous kidneys and normal tissues(P<0.05) and no significant differences of PR and ER were found between autologous and normal kidneys(P>0.05). The level and positive rate of PR in stage Ⅰ were higher than those in stage Ⅱ to Ⅳ of RCC tissues (P<0.05). There was no relationship between the status of PR, ER and patient sex(P>0.05). Expression of PR in RCC had correlation to Robson stage closely. The positive rate of PR may be treated as a prognostic factor because it decreased as the stage rose. Our result provided an experimental basis for the application of hormonal therapy in RCC and emphasized that patients who may be benefited from hormonal therapy must have sufficient hormone receptors.

The effect of Chinese herbal medicine“heche assisted pregnancy recipe”on endometrial estrogen and progesterone receptor,proliferating cell nuclear antigen and vascular endothelial growth factor in the patients with infertility

Objectives:To investigate the effect of Chinese herbal medicine"heche assisted preg-nancy recipe (HCAPR)" on estrogen receptor(ER), progesterone receptor (PR), pro-lifierating cell nuclear antigen(PCNA) and vascular endothelial growth factor (VEGF)in endometrium of infertile women.Methods: The S-P immunohistochemical assay was used to observe expression ofER, PR , PCNA and VEGF in late proliferative phase before and after the HCAPR treat-ment.Results: After the treatment, the expression of ER,PR,PCNA and VEGF in nucleiof glandular epithelium and stromal cells was significantly stronger (all P＜0. 001) re-spectively than that before treatment , especially the expression of PCNA and VEGF.Conclusions: These results suggest that traditional Chinese medicine HCAPR oftonifying kidney and regulating menstruation increased the synthesis of ER,PR, PCNAand VEGF, which may promote normal growth and development of the endometrium ,improve the micro-environment of the endometrium, and enhance uterine receptivity.The evidence may provide theoretical basis for therapy infertility with Chinese herbalmedicine.

Effect of Mifepristone and Anordrin Compound on Levels of Estrogen and Progesterone Receptor mRNAs in Human Decidua of Early Pregnancy

To provide the theoretical fundation for the further clinical application of mifepristone and anordrin compound. Materials & Methods Ribonuclease protection assay was used for the detection and quantitation of estrogen and progesterone receptor mRNAs in human decidua from the termination of early pregnancy.Three groups, each of which had 6～8 cases, were studied. Results Compared to the normal control group, estrogen and progesterone receptor mRNAs increased significantly (P<0.05) in the mifepristone group, whereas the changes in the group administrated mifepristone compound which contains anordrin were not obvious. Conclusions The result suggests that with the similar clinical effect, mifepristone compound has less side effect on the patients, thus being more suitable for the anti early pregnancy drug.

Determination of Progesterone Receptor by Chemiluminescent Enzyme Immunoassay

A new method of chemiluminescent enzyme immunoassay (CLEIA) was developed and the standard curve and regression equation for determination of progesterone receptor (PR) made. The luminosity of tissue samples was tested and PR level was calculated by the regression equation. Correlation analysis revealed that there was a linear relationship between different concentrations of the standard PR samples and the corresponding values of luminosity: Y=3748+463.77X, γ=0 9958. The values of the luminosity in 38 cases of tumor tissues were determined with the highest being 267.32 fmol/mg, the lowest 3.69 fmol/mg and the mean 78.53 fmol/mg. The new method of CLEIA was a stable, creditable,specific and sensitive assay for determination of PR.

Collagen types in relation to expression of estradiol and progesterone receptors in equine endometrial fibrosis

The aim of this study was to determine the influence of collagen I and III on the expression of estrogen and progesterone receptors in equine endometrial fibrosis. A total of 25 crossbred mares were studies. Two endometrial samples were collected from each mare,1 inthe estrus and1 inthe diestrus phase. The samples were classified according to histological changes. Collagen was typed and quantified using the picrosirius red histochemical technique, and steroid receptors were identified by immunohistochemistry. The results showed a predominance of collagen type III in all the endometrial samples. The expression of estrogen (RE2) and progesterone (RP4) receptors varied according to the estrous cycle. RE2 and RP4 expression varied in the estrus and diestrus phases;there was no influence of collagen I or II on receptor expression.

Correlation of Hormonal Receptors Estrogen Receptor, Progesterone Receptor and Her-2/Neu with Tumor Characteristics in Breast Carcinoma: Study of 100 Consecutive Cases

Introduction-Breast cancer is the most common cancer and leading cause of death in women. In India, its incidence is rapidly rising over last few decades. Present study is aimed to study the pattern of expression of hormonal receptors and Her-2/neu in invasive breast carcinoma and to correlate estrogen receptor (ER), progesterone receptor (PR) and Her-2/neu expressions with various clinicopathological parameters. Material and methods: The present study was carried out in Department of Pathology, S.C.B. Medical College, Cuttack in the year 2013 taking consecutive 100 cases. Routine H&E staining for histological diagnosis and IHC analysis for ER, PR and Her 2/neu was carried out in all 100 cases of breast malignancies. Results: 99% of cases are invasive breast carcinoma, not otherwise specify (IDC-NOS). The age ranges from 23 years to 72 years. Majority of tumors are of grade 2 (70%) followed by grade 3 (30%). ER PR and Her-2/neu expression are seen in 45%, 35% and 30% respectively. Triple negative cases comprise 35%. Higher number of grade 2 tumor shows ER, PR positivity as compared to grade 3 tumors. Her-2/neu expression does not show any significant correlation with age or lymph node status of the patient. Conclusion: ER and PR expression in breast cancers in the current study are found to be comparable to the findings of other authors, but the frequency of HER-2/neu expression is slightly higher. Significant correlation is observed between hormonal receptor status and the grade of the tumor. Inverse relationship is found between Her-2/neu expression and ER, PR receptor status. Her-2/neu expression is increased with size and high grade of tumor.