Follicular fluid C3a-peptide promotes oocyte maturation through F-actin aggregation.

BACKGROUND: Immature cumulus-oocyte complexes are retrieved to obtain mature oocytes by in vitro maturation (IVM), a laboratory tool in reproductive medicine to obtain mature oocytes. Unfortunately, the efficiency of IVM is not satisfactory. To circumvent this problem, we therefore intended to commence with the composition of ovarian follicular fluid (FF), an important microenvironment influencing oocyte growth. It is well known that FF has a critical role in oocyte development and maturation. However, the components in human FF remain largely unknown, particularly with regard to small molecular peptides. RESULTS: In current study, the follicular fluid derived from human mature and immature follicles were harvested. The peptide profiles of FF were further investigated by using combined ultrafiltration and LC-MS/MS. The differential peptides were preliminary determined by performing differentially expressed analysis. Human and mouse oocyte culture were used to verify the influence of differential peptides on oocyte development. Constructing plasmids, cell transfecting, Co-IP, PLA etc. were used to reveal the detail molecular mechanism. The results from differentially expressed peptide as well as cultured human and mouse oocytes analyses showed that highly conserved C3a-peptide, a cleavage product of complement C3a, definitely affected oocytes development. Intriguingly, C3a-peptide possessed a novel function that promoted F-actin aggregation and spindle migration, raised the percentage of oocytes at the MII stage, without increasing the chromosome aneuploidy ratio, especially in poor-quality oocytes. These effects of C3a-peptide were attenuated by C3aR morpholino inhibition, suggesting that C3a-peptide affected oocytes development by collaborating with its classical receptor, C3aR. Specially, we found that C3aR co-localized to the spindle with ß-tubulin to recruit F-actin toward the spindle and subcortical region of the oocytes through specific binding to MYO10, a key regulator for actin organization, spindle morphogenesis and positioning in oocytes. CONCLUSIONS: Our results provide a new perspective for improving IVM culture systems by applying FF components and also provide molecular insights into the physiological function of C3a-peptide, its interaction with C3aR, and their roles in enabling meiotic division of oocytes.

CD4+ICOS+Foxp3+: a sub-population of regulatory T cells contribute to malaria pathogenesis.

BACKGROUND: Regulatory T cells are known to play a key role to counter balance the protective immune response and immune mediated pathology. However, the role of naturally occurring regulatory cells CD4+CD25+Foxp3+ in malaria infection during the disease pathogenesis is controversial. Beside this, ICOS molecule has been shown to be involved in the development and function of regulatory T cell enhance IL-10 production. Therefore, possible involvement of the ICOS dependent regulatory CD4+ICOS+Foxp3+ T cells in resistance/susceptibility during malaria parasite is explored in this study. METHODS: 5 × 105 red blood cells infected with non-lethal and lethal parasites were inoculated in female Balb/c mice by intra-peritoneal injection. Infected or uninfected mice were sacrificed at early (3rd day post infection) and later stage (10th day post infection) of infection. Harvested cells were analysed by using flow cytometer and serum cytokine by Bioplex assay. RESULTS: Thin blood films show that percentages of parasitaemia increases with disease progression in infections with the lethal malaria parasite and mice eventually die by day 14th post-infection. Whereas in case of non-lethal malaria parasite, parasitaemia goes down by 7th day post infection and gets cleared within 13th day. The number of CD4+ ICOS+ T cells increases in lethal infection with disease progression. Surprisingly, in non-lethal parasite, ICOS expression decreases after day 7th post infection as parasitaemia goes down. The frequency of CD4+ICOS+FoxP3+ Tregs was significantly higher in lethal parasitic infection as compared to the non-lethal parasite. The level of IL-12 cytokine was remarkably higher in non-lethal infection compared to the lethal infection. In contrast, the level of IL-10 cytokines was higher in lethal parasite infection compared to the non-lethal parasite. CONCLUSION: Taken together, these data suggest that lethal parasite induce immunosuppressive environment, protecting from host immune responses and help the parasite to survive whereas non-lethal parasite leads to low frequencies of Treg cells seldom impede immune response that allow the parasite to get self-resolved.

Participation of angiotensin-(1-7) in exercise-induced analgesia in rats with neuropathic pain.

Exercise reduces neuropathic pain in animals and humans. Recent studies indicate that training exercise favors the synthesis and action of angiotensin-(1-7) (Ang-(1-7)), a vasoactive peptide of the renin-angiotensin system (RAS), in various tissues. Interestingly, Ang-(1-7) also relieves neuropathic pain; however, it remains to be elucidated whether exercise mitigates this type of pain through Ang-(1-7). In this study, we investigated the role of Ang-(1-7) in exercise-induced analgesia in a neuropathic pain model. Male Wistar rats were ligated of lumbar spinal nerves (L5 and L6) or sham-operated. Then, they were subjected to acute (2-h) or chronic (4-week) exercise protocols. Tactile allodynia was evaluated before and after each exercise intervention. Microosmotic pumps were implanted subcutaneously for the release of Ang-(1-7) or A779 (selective Mas receptor (MasR; Ang-(1-7) receptor) antagonist). Plasma levels of Ang II and Ang-(1-7) were quantified by HPLC. Spinal nerve ligation (SNL) produced tactile allodynia. Both acute and chronic exercise reversed this neuropathic behavior. A779 treatment prevented the antiallodynic effect induced by each exercise protocol. SNL increased the plasma Ang II/Ang-(1-7) ratio; however, exercise did not modify it. Acute treatment with Ang-(1-7) via MasR mimicked exercise-mediated antinociception. Collectively, these results suggest that activation of the Ang-(1-7)/MasR axis of the RAS represents a potential novel mechanism by which exercise attenuates neuropathic pain in rats.

Mendelian randomization study of the relation between adiponectin and heart function, unravelling the paradox.

High adiponectin concentrations are generally regarded as beneficial with regard to cardiometabolic health, but have been paradoxically associated with increased cardiovascular disease risk, specifically heart failure, in individuals at high cardiovascular risk. We aimed to investigate the association between adiponectin and heart function parameters, and inversely, we estimated the effect of genetically-determined heart function and NT-proBNP as the main marker of heart failure on adiponectin using Mendelian randomisation. Observational analyses between adiponectin and measures of heart function, i.e. E/A ratio, left, and right ventricular ejection fraction, were performed in participants of the Netherlands Epidemiology of Obesity (NEO) study, assessed by MRI of the heart (n = 1,138). Two-sample Mendelian randomisation analyses were conducted to estimate the effect of NT-proBNP and heart function on adiponectin concentrations using publicly-available summary statistics (ADIPOGen; the PLATO trial). The mean (standard deviation) age was 56 (6) years and mean body mass index was 26 (4) kg/m2. Per five µg/mL higher adiponectin, the E/A ratio was -0.05 (95 % CI: -0.10, -0.01) lower, left ventricle ejection fraction was -0.5 % (95 % CI: -1.1, 0.1) lower, and right ventricle ejection fraction was 0.5 % (95 % CI: -0.1, 1.2) higher. Genetically-determined NT-proBNP was causally related to adiponectin concentrations in ADIPOGen: per doubling of genetically-determined NT-proBNP, adiponectin concentrations were 11.4 % (95 % CI: 1.7, 21.6) higher. With causal MR methods we showed that NT-proBNP affects adiponectin concentrations, while adiponectin is not associated with heart function parameters. Therefore, reverse causation may explain the adiponectin paradox observed in previous studies.

Oligomeric and Fibrillar Species of Aß42 Diversely Affect Human Neural Stem Cells.

Amyloid-ß 42 peptide (Aß1-42 (Aß42)) is well-known for its involvement in the development of Alzheimer's disease (AD). Aß42 accumulates and aggregates in fibers that precipitate in the form of plaques in the brain causing toxicity; however, like other forms of Aß peptide, the role of these peptides remains unclear. Here we analyze and compare the effects of oligomeric and fibrillary Aß42 peptide on the biology (cell death, proliferative rate, and cell fate specification) of differentiating human neural stem cells (hNS1 cell line). By using the hNS1 cells we found that, at high concentrations, oligomeric and fibrillary Aß42 peptides provoke apoptotic cellular death and damage of DNA in these cells, but Aß42 fibrils have the strongest effect. The data also show that both oligomeric and fibrillar Aß42 peptides decrease cellular proliferation but Aß42 oligomers have the greatest effect. Finally, both, oligomers and fibrils favor gliogenesis and neurogenesis in hNS1 cells, although, in this case, the effect is more prominent in oligomers. All together the findings of this study may contribute to a better understanding of the molecular mechanisms involved in the pathology of AD and to the development of human neural stem cell-based therapies for AD treatment.

The Gliopeptide ODN, a Ligand for the Benzodiazepine Site of GABAA Receptors, Boosts Functional Recovery after Stroke.

Following stroke, the survival of neurons and their ability to reestablish connections is critical to functional recovery. This is strongly influenced by the balance between neuronal excitation and inhibition. In the acute phase of experimental stroke, lethal hyperexcitability can be attenuated by positive allosteric modulation of GABAA receptors (GABAARs). Conversely, in the late phase, negative allosteric modulation of GABAAR can correct the suboptimal excitability and improves both sensory and motor recovery. Here, we hypothesized that octadecaneuropeptide (ODN), an endogenous allosteric modulator of the GABAAR synthesized by astrocytes, influences the outcome of ischemic brain tissue and subsequent functional recovery. We show that ODN boosts the excitability of cortical neurons, which makes it deleterious in the acute phase of stroke. However, if delivered after day 3, ODN is safe and improves motor recovery over the following month in two different paradigms of experimental stroke in mice. Furthermore, we bring evidence that, during the subacute period after stroke, the repairing cortex can be treated with ODN by means of a single hydrogel deposit into the stroke cavity.SIGNIFICANCE STATEMENT Stroke remains a devastating clinical challenge because there is no efficient therapy to either minimize neuronal death with neuroprotective drugs or to enhance spontaneous recovery with neurorepair drugs. Around the brain damage, the peri-infarct cortex can be viewed as a reservoir of plasticity. However, the potential of wiring new circuits in these areas is restrained by a chronic excess of GABAergic inhibition. Here we show that an astrocyte-derived peptide, can be used as a delayed treatment, to safely correct cortical excitability and facilitate sensorimotor recovery after stroke.

SARS-CoV-2 infection in alpha1-antitrypsin deficiency.

Alpha1-antitrypsin deficiency arises due to mutations in alpha1-antitrypsin (AAT) gene and represents the most prominent genetic predisposition to chronic obstructive pulmonary disease and emphysema. Since AAT plays important immunomodulatory and tissue-protective roles and since it was suggested to protect from severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, we assessed this association in United Kingdom Biobank, a community-based cohort with >500,000 participants. The most common, mild AATD genotypes were associated neither with increased SARS-CoV-2 infection rates nor with increased SARS-CoV-2 fatalities, while the numbers of severe AATD cases were too low to allow definitive conclusions.

Amplifying effect of chronic lisinopril therapy on diastolic function and the angiotensin-(1-7) Axis by the G1 agonist in ovariectomized spontaneously hypertensive rats.

G protein-coupled estrogen receptor (GPER) activation by G1 attenuates diastolic dysfunction from estrogen loss, which may be partly due to suppression of angiotensin II pathological actions. We aimed to determine the independent effects of 8 weeks of G1 (100 µg/kg/d, subcutaneous pellet), ACE-inhibition (ACEi; lisinopril 10 mg/kg, drinking water), or combination therapy versus vehicle in the ovariectomized (OVX) spontaneously hypertensive rat (SHR) on cardiac function and morphometrics (echocardiography), serum equilibrium of angiotensins (mass spectroscopy) and cardiac components of the RAS (Western blotting). G1 alone and when combined with ACEi enhanced myocardial relaxation (é: 30 and 17%) and diastolic wall strain (DWS: 76 and 68%) while reducing relative wall thickness (RWT: 20 and 33%) and filling pressures (E/é: 30 and 37%). Cardiac expression levels of Mas receptor (Mas-R) and ACE2 also increased in the presence of G1. Strong antihypertensive effects of lisinopril monotherapy were associated with reductions in RWT, collagen deposition and E/é without overtly altering é or DWS. Chronic ACEi also increased cardiac levels of Mas-R and AT1-R and tilted the circulating RAS toward the formation of Ang-(1-7), which was amplified in the presence of G1. In vitro studies further revealed that an inhibitor to prolyl endopeptidase (PEP), but not to neprilysin, significantly reduced serum Ang-(1-7) levels in G1-treated rats, suggesting that G1 might be increasing Ang-(1-7) formation via PEP. We conclude that activating GPER with G1 augments components of the cardiac RAS and improves diastolic function without lowering blood pressure, and that lisinopril-induced blood pressure control and cardiac alterations in OVX SHR are permissive in facilitating G1 to augment Ang-(1-7) in serum, thereby strengthening its cardioprotective benefits.

Cytoplasmic short linear motifs in ACE2 and integrin ß3 link SARS-CoV-2 host cell receptors to mediators of endocytosis and autophagy.

The spike protein of SARS-CoV-2 binds the angiotensin-converting enzyme 2 (ACE2) on the host cell surface and subsequently enters host cells through receptor-mediated endocytosis. Additional cell receptors may be directly or indirectly involved, including integrins. The cytoplasmic tails of ACE2 and integrins contain several predicted short linear motifs (SLiMs) that may facilitate internalization of the virus as well as its subsequent propagation through processes such as autophagy. Here, we measured the binding affinity of predicted interactions between SLiMs in the cytoplasmic tails of ACE2 and integrin ß3 with proteins that mediate endocytic trafficking and autophagy. We validated that a class I PDZ-binding motif mediated binding of ACE2 to the scaffolding proteins SNX27, NHERF3, and SHANK, and that a binding site for the clathrin adaptor AP2 µ2 in ACE2 overlaps with a phospho-dependent binding site for the SH2 domains of Src family tyrosine kinases. Furthermore, we validated that an LC3-interacting region (LIR) in integrin ß3 bound to the ATG8 domains of the autophagy receptors MAP1LC3 and GABARAP in a manner enhanced by LIR-adjacent phosphorylation. Our results provide molecular links between cell receptors and mediators of endocytosis and autophagy that may facilitate viral entry and propagation.

NC1-peptide derived from collagen α3 (IV) chain is a blood-tissue barrier regulator: lesson from the testis.

Collagen α3 (IV) chains are one of the major constituent components of the basement membrane in the mammalian testis. Studies have shown that biologically active fragments, such as noncollagenase domain (NC1)-peptide, can be released from the C-terminal region of collagen α3 (IV) chains, possibly through the proteolytic action of metalloproteinase 9 (MMP9). NC1-peptide was shown to promote blood-testis barrier (BTB) remodeling and fully developed spermatid (e.g., sperm) release from the seminiferous epithelium because this bioactive peptide was capable of perturbing the organization of both actin- and microtubule (MT)-based cytoskeletons at the Sertoli cell-cell and also Sertoli-spermatid interface, the ultrastructure known as the basal ectoplasmic specialization (ES) and apical ES, respectively. More importantly, recent studies have shown that this NC1-peptide-induced effects on cytoskeletal organization in the testis are mediated through an activation of mammalian target of rapamycin complex 1/ribosomal protein S6/transforming retrovirus Akt1/2 protein (mTORC1/rpS6/Akt1/2) signaling cascade, involving an activation of cell division control protein 42 homolog (Cdc42) GTPase, but not Ras homolog family member A GTPase (RhoA), and the participation of end-binding protein 1 (EB1), a microtubule plus (+) end tracking protein (+TIP), downstream. Herein, we critically evaluate these findings, providing a critical discussion by which the basement membrane modulates spermatogenesis through one of its locally generated regulatory peptides in the testis.

Hemopressin as a breakthrough for the cannabinoid field.

Hemopressin (PVNFKFLSH in rats, and PVNFKLLSH in humans and mice), a fragment derived from the α-chain of hemoglobin, was the first peptide described to have type 1 cannabinoid receptor activity. While hemopressin was shown to have inverse agonist/antagonistic activity, extended forms of hemopressin (i.e. RVD-hemopressin, also called pepcan-12) exhibit type 1 and type 2 cannabinoid receptor agonistic/allosteric activity, and recent studies suggest that they can activate intracellular mitochondrial cannabinoid receptors. Therefore, hemopressin and hemopressin-related peptides could have location-specific and biased pharmacological action, which would increase the possibilities for fine-tunning and broadening cannabinoid receptor signal transduction. Consistent with this, hemopressins were shown to play a role in a number of physiological processes including antinociceptive and anti-inflammatory activity, regulation of food intake, learning and memory. The shortest active hemopressin fragment, NFKF, delays the first seizure induced by pilocarpine, and prevents neurodegeneration in an experimental model of autoimmune encephalomyelitis. These functions of hemopressins could be due to engagement of both cannabinoid and non-cannabinoid receptor systems. Self-assembled nanofibrils of hemopressin have pH-sensitive switchable surface-active properties, and show potential as inflammation and cancer targeted drug-delivery systems. Upon disruption of the self-assembled hemopressin nanofibril emulsion, the intrinsic analgesic and anti-inflammatory properties of hemopressin could help bolster the therapeutic effect of anti-inflammatory or anti-cancer formulations. In this article, we briefly review the molecular and behavioral pharmacological properties of hemopressins, and summarize studies on the intricate and unique mode of generation and binding of these peptides to cannabinoid receptors. Thus, the review provides a window into the current status of hemopressins in expanding the repertoire of signaling and activity by the endocannabinoid system, in addition to their new potential for pharmaceutic formulations.

The prognostic value of Presepsin for postoperative complications following pancreatic resection: A prospective study.

BACKGROUND: Presepsin is involved in binding lipopolysaccharides and previous studies have confirmed its value as a marker for early diagnosis and prediction of severity in sepsis. Comparable studies assessing the predictive potential regarding postoperative complications and mortality following pancreatic resection are lacking. METHODS: This prospective study included 70 patients undergoing pancreatic resection from December 2017 until May 2019. Presepsin was measured preoperatively, on postoperative day 1, 3 and 8 (POD1/3/8) and correlated with the clinical course and mortality. RESULTS: Severe complications (Clavien-Dindo ≥3a) occurred in 28 patients (40%), postoperative pancreatic fistula (POPF) grade B/C occurred in 20 patients (28.6%), infectious complications in 28 (40%), and four patients (5.7%) died during hospital stay. Presepsin levels at any timepoint did not correlate with further development of postoperative complications or in-hospital mortality whereas CRP levels on postoperative day (POD) 3 were significantly associated with clinically relevant POPF (AUC 0.664, 95%CI 0.528-0.800; p = 0.033). Preoperative Presepsin levels as well as Presepsin on POD1 were significantly elevated in patients with malignant compared to benign underlying disease (299pg/ml vs. 174pg/ml and 693.5pg/ml vs. 294pg/ml; p = 0.009 and 0.013, respectively). CONCLUSION: In our cohort, Presepsin was not eligible to predict the postoperative course following pancreatic resection. However, Presepsin levels were significantly elevated in patients with malignant disease, this finding warrants further investigation.

Blockade of Glial Connexin 43 Hemichannels Reduces Food Intake.

The metabolic syndrome, which comprises obesity and diabetes, is a major public health problem and the awareness of energy homeostasis control remains an important worldwide issue. The energy balance is finely regulated by the central nervous system (CNS), notably through neuronal networks, located in the hypothalamus and the dorsal vagal complex (DVC), which integrate nutritional, humoral and nervous information from the periphery. The glial cells' contribution to these processes emerged few year ago. However, its underlying mechanism remains unclear. Glial connexin 43 hemichannels (Cx43 HCs) enable direct exchange with the extracellular space and can regulate neuronal network activity. In the present study, we sought to determine the possible involvement of glial Cx43 HCs in energy balance regulation. We here show that Cx43 is strongly expressed in the hypothalamus and DVC and is associated with glial cells. Remarkably, we observed a close apposition of Cx43 with synaptic elements in both the hypothalamus and DVC. Moreover, the expression of hypothalamic Cx43 mRNA and protein is modulated in response to fasting and diet-induced obesity. Functionally, we found that Cx43 HCs are largely open in the arcuate nucleus (ARC) from acute mice hypothalamic slices under basal condition, and significantly inhibited by TAT-GAP19, a mimetic peptide that specifically blocks Cx43 HCs activity. Moreover, intracerebroventricular (i.c.v.) TAT-GAP19 injection strongly decreased food intake, without further alteration of glycaemia, energy expenditures or locomotor activity. Using the immediate early gene c-Fos expression, we found that i.c.v. TAT-GAP19 injection induced neuronal activation in hypothalamic and brainstem nuclei dedicated to food intake regulation. Altogether, these results suggest a tonic delivery of orexigenic molecules associated with glial Cx43 HCs activity and a possible modulation of this tonus during fasting and obesity.

Countermeasure and therapeutic: A(1-7) to treat acute respiratory distress syndrome due to COVID-19 infection.

In the wake of the COVID-19 pandemic it has become clear that there is a need for therapies that are capable of reducing damage caused to patients from infections. Infections that induce Acute Respiratory Distress Syndrome (ARDS) are especially devastating because lung damage is so critical and difficult to manage. Angiotensin (1-7) [A(1-7)] has already been shown to protect pulmonary health and architecture in various models of disease. There is also evidence that A(1-7) can modulate immune function and protect various organs (lung, kidney, and heart) from oxidative damage and inflammation. Here we focus on making a case for the development of novel therapies that target the protective arm of the Renin Angiotensin System (RAS).

Carboxyl-terminal polypeptide fragment of MUC16 combing stathmin1 promotes gallbladder cancer cell migration and invasion.

CA-125, coded by MUC16 gene, is responsible to many kinds of tumor metastasis. However, the related mechanism remains unclear. We have established a novel manner to reveal gallbladder cancer metastasis related to serum CA-125 levels through the C-terminal polypeptide of MUC16 gene production. MUC16 C-terminal polypeptide significantly promoted gallbladder cancer cell migration and invasion in vitro. Mass spectrum indicated that interaction of MUC16 C-terminal fragment with the C-terminal domain of stathmin1 inhibited the phosphorylation of stathmin1 to promote the combination with tubulin. Stathmin1 knockdown inhibited the migration and invasion of gallbladder cancer cells in vitro and lung metastasis in vivo induced by MUC16 C-terminal polypeptide. The high expression level of MUC16c consistent with stathmin1 was also confirmed in gallbladder cancer tissues. Our study revealed the underlying mechanism of gallbladder cancer metastasis related to CA-125 levels, which was beneficial for CA-125 in gallbladder cancer diagnose and therapy.

GIP(3-30)NH2 - a tool for the study of GIP physiology.

Glucose-dependent insulinotropic polypeptide (GIP) is a gut hormone impacting glucose, lipid and bone metabolism through the GIP receptor (GIPR). The GIP system has key species differences complicating the translation of findings from rodent to human physiology. Furthermore, the effects of endogenous GIP in humans have been difficult to tease out due to the lack of a suitable GIPR antagonist. The naturally occurring GIP(3-30)NH2 has turned out to constitute a safe and efficacious GIPR antagonist for rodent and human use. To study GIP physiology, it is recommended to use the species-specific GIP(3-30)NH2 peptide sequence, and for human intravenous infusions, an antagonist:agonist ratio of a minimum of 600 with a 20min infusion time before the intervention of interest is recommended. Several studies using GIP(3-30)NH2 are coming, hopefully providing new insights into the physiology of GIP, the pathophysiologic involvement of GIP in several diseases and the therapeutic potential of the GIPR.

Dynamic changes in the brain protein interaction network correlates with progression of Aß42 pathology in Drosophila.

Alzheimer's disease (AD), the most prevalent form of dementia, is a progressive and devastating neurodegenerative condition for which there are no effective treatments. Understanding the molecular pathology of AD during disease progression may identify new ways to reduce neuronal damage. Here, we present a longitudinal study tracking dynamic proteomic alterations in the brains of an inducible Drosophila melanogaster model of AD expressing the Arctic mutant Aß42 gene. We identified 3093 proteins from flies that were induced to express Aß42 and age-matched healthy controls using label-free quantitative ion-mobility data independent analysis mass spectrometry. Of these, 228 proteins were significantly altered by Aß42 accumulation and were enriched for AD-associated processes. Network analyses further revealed that these proteins have distinct hub and bottleneck properties in the brain protein interaction network, suggesting that several may have significant effects on brain function. Our unbiased analysis provides useful insights into the key processes governing the progression of amyloid toxicity and forms a basis for further functional analyses in model organisms and translation to mammalian systems.

Tau knockout exacerbates degeneration of parvalbumin-positive neurons in substantia nigra pars reticulata in Parkinson's disease-related α-synuclein A53T mice.

α-Synuclein (α-syn)-induced neurotoxicity has been generally accepted as a key step in the pathogenesis of Parkinson's disease (PD). Microtubule-associated protein tau, which is considered second only to α-syn, has been repeatedly linked with PD in association studies. However, the underlying interaction between these two PD-related proteins in vivo remains unclear. To investigate how the expression of tau affects α-syn-induced neurodegeneration in vivo, we generated triple transgenic mice that overexpressed α-syn A53T mutation in the midbrain dopaminergic neurons (mDANs) with different expression levels of tau. Here, we found that tau had no significant effect on the A53T α-syn-mediated mDANs degeneration. However, tau knockout could modestly promote the formation of α-syn aggregates, accelerate the severe and progressive degeneration of parvalbumin-positive (PV+) neurons in substantia nigra pars reticulata (SNR), accompanied with anxiety-like behavior in aged PD-related α-syn A53T mice. The mechanisms may be associated with A53T α-syn-mediated specifically successive impairment of N-methyl-d-aspartate receptor subunit 2B (NR2B), postsynaptic density-95 (PSD-95) and microtubule-associated protein 1A (MAP1A) in PV+ neurons. Our study indicates that MAP1A may play a beneficial role in preserving the survival of PV+ neurons, and that inhibition of the impairment of NR2B/PSD-95/MAP1A pathway, may be a novel and preferential option to ameliorate α-syn-induced neurodegeneration.

Genistein inhibits amyloid peptide 25-35-induced neuronal death by modulating estrogen receptors, choline acetyltransferase and glutamate receptors.

PURPOSE: To explore genistein, the most active component of soy isoflavones, on viability, expression of estrogen receptor (ER) subtypes, choline acetyltransferase (ChAT), and glutamate receptor subunits in amyloid peptide 25-35-induced hippocampal neurons, providing valuable data and basic information for neuroprotective effect of genistein in Aß25-35-induced neuronal injury. METHODS: We established an in vitro model of Alzheimer's disease by exposing primary hippocampal neurons of newborn rats to amyloid peptide 25-35 (20 µM) for 24 h and observing the effects of genistein (10 µM, 3 h) on viability, expression of ER subtypes, ChAT, NMDA receptor subunit NR2B and AMPA receptor subunit GluR2 in Aß25-35-induced hippocampal neurons. RESULTS: We found that amyloid peptide 25-35 exposure reduced the viability of hippocampal neurons. Meanwhile, amyloid peptide 25-35 exposure decreased the expression of ER subtypes, ChAT and GluR2, and increased the expression of NR2B. Genistein at least partially reversed the effects of amyloid peptide 25-35 in hippocampal neurons. CONCLUSION: Genistein could increase the expression of ChAT as a consequence of activating estrogen receptor subtypes, modulating the expression of NR2B and GluR2, and thereby ameliorating the status of hippocampal neurons and exerting neuroprotective effects against amyloid peptide 25-35. Our data suggest that genistein might represent a potential cell-targeted therapy which could be a promising approach to treating AD.