19 results about "Aβ oligomers" patented technology

Provided is a new and highly toxic amyloid oligomer Aβo*3F. The Aβo*3F is specifically bound by a 3F antibody, is the most important toxic ingredient in a mixture of Aβ oligomers, and has a strong pathogenic effect. Further provided is a binding agent that specifically binds to Aβo*3F, a composition containing Aβo*3F, and a use of Aβo*3F as a target in the prevention and / or treatment and / or diagnosis of MCI and / or AD in subjects.

A use of a new highly toxic amyloid oligomer Apo*3F as a target for diagnosing Alzheimer's disease (AD) in the early stage and the middle-late stage and mild cognitive impairment (MCI) caused by AD. The Aβo*3F specifically binds to an antibody 3F and is present in cerebrospinal fluid (CSF), blood and / or brain tissue of AD patients and patients with MCI caused by AD, and the levels show highly significant differences in CSF, blood and / or brain tissue of AD patients, MCI patients and healthy elderly persons. In addition, the Apo*3F is an ultra-highly toxic oligomer, is the most important toxic component in an Aβ oligomer mixture, has a strong pathogenic effect, and plays a key role in the occurrence and development of AD.

The invention discloses a kit for detecting an A beta oligomer. The kit comprises a nucleic acid aptamer-activator modified streptavidin magnetic bead, a methylene blue nucleic acid signal probe modified streptavidin magnetic bead, a Cas12a-crRNA compound and a synthetic gold nanocluster probe modified glassy carbon electrode. According to the invention, the beta-CD-AuNCs probe with high quantum yield is used as an electrochemiluminescence material, methylene blue is used as an electrochemiluminescence quencher, and through combination with CRISPR / Cas technology, signal change of an ECL reaction system is effectively regulated and controlled, and AbetaO detection is realized. The method has the advantages of strong detection specificity, good selectivity, high sensitivity and strong anti-interference capability on AbetaO, and has good market value.

The present invention relates to an isoindol-sulfilimine compound and its preparation and its use as a sigma-2 receptor inhibitor. Compared with the prior art, the isoindol-sulfilimine compound prepared by the present invention can effectively inhibit the sigma-2 receptor activity by binding to the sigma-2 receptor and deformationally regulating the sigma-2 receptor complex, which will lead to the instability of the binding of adjacent Aβ oligomers to the receptor on the synapse, thus leading to the removal of AB oligomers from the synapse. It can be further used for the preparation of new therapeutic drugs for tumor and neurodegenerative diseases.

This invention discloses a method for preparing NK cells, the NK cells obtained thereby, and their applications. The method includes: sorting NK cells from peripheral blood of an allogeneic donor; culturing them in a serum-free medium containing CD3 monoclonal antibody, CD16 antibody, and IL-2, without the need for a feeder layer; preferably, IL-21 is added for amplification on days 3-5 of culture, and the cells are cultured for 20-40 days. This method yields non-genetically modified NK cells, among which CD56... bright The NK cells comprise >90% of the cell line and highly express a variety of activating and functional molecules. These NK cells effectively clear Aβ oligomers and senescent cells, and alleviate neuroinflammation. In treatment, intracranial injection achieves equivalent or better efficacy with only about 1 / 10th the dose administered intravenously, significantly clearing Aβ deposits in the brains of AD model mice and improving pathology.

The invention discloses calf animal coccus PD13 for improving Alzheimer's disease and application of the calf animal coccus PD13, and relates to the technical field of biology. Experiments prove that in an Alzheimer's disease model mouse induced by injecting A beta oligomer into the brain, the Azococcus calvus PD13 can improve spatial learning and memory disorder and autonomous exploration ability of the AD model mouse and relieve damage to neurons in a hippocampal region of the Alzheimer's disease model mouse, so that the effect of protecting the neurons is achieved, and the Azococcus calvus PD13 can be used for preparing a medicine for treating the Alzheimer's disease. According to the present invention, with the application of the animal coccus calves, the content of glutathione in mouse serum and the enzyme activity of superoxide dismutase are increased, and the content of malondialdehyde is reduced, such that the animal coccus calves provides good prevention and treatment effects on the Alzheimer's disease, and the new approach is provided for developing the Alzheimer's disease-related drugs.

The present invention discloses a method for preparing a fusion protein for targeted treatment of Alzheimer's disease and a delivery system thereof. The present invention connects the RING type + B box type domain in the TRIM21 protein with an antibody or nanobody targeting Aβ oligomers through a linker, constructs a bispecific fusion protein, selects AAV9 with neurophagocytic properties as a delivery vector for the nucleic acid sequence of the bispecific fusion protein, and mediates the expression of the anti-Aβ oligomer bispecific fusion protein to achieve long-term stable expression in vivo, and its expression product can specifically recognize Aβ oligomers and activate the ubiquitination degradation system, so as to achieve the purpose of long-term specific removal of Aβ oligomers in vivo, thereby achieving the treatment of AD.

This invention provides an Alzheimer's disease risk assessment system, comprising: a data acquisition module for acquiring test data of subjects, the test data including at least the concentration of Aβ oligomers, APOEε4 gene carrier status data, and multi-domain risk factor data; the multi-domain risk factor data including demographic indicators and clinical data related to Alzheimer's disease risk; a risk assessment module, communicatively connected to the data acquisition module, for taking the test data from the data acquisition module as input, and outputting a risk probability value of the subject having Alzheimer's disease through a pre-trained machine learning model; and a result output module, communicatively connected to the risk assessment module, for comparing the risk probability value with a preset threshold and outputting risk classification information based on the comparison result. This invention is the first to achieve high-precision and high-sensitivity clinical cognitive impairment screening by fusing multidimensional conventional data through a nonlinear model.

Herein is disclosed amphiphilic small molecules with different hydrophobic and hydrophilic fragments that show high M binding affinity to both Aβ plaques and oligomers, and selectively binding Aβ oligomers. These amphiphilic compounds can also label the Aβ species in the brain sections of transgenic AD mice, as shown by immunostaining with an Aβ antibody. Certain amphiphilic compounds were found to alleviate the Cu2+-Aβ induced toxicity in cell viability assays. Additionally, two compounds, ZY-15-MT and ZY-15-OMe, were found to disrupt the interactions between Aβ oligomers and human neuroblastoma SH-SY5Y cell membranes. These studies show compounds with amphiphilic properties that target Aβ oligomers and modulate the Aβ oligomer-cell membrane interactions can be effective as small molecule AD therapeutics. Also, the disclosed amphiphilic dicyanomethylene compounds that can emit in the near-infrared region and chelate copper can be used as early diagnostic agents for AD.

The invention relates to application of an exosome derived from olfactory mucosa mesenchymal stem cells pretreated based on active peptide in improvement of neuroinflammation, in particular to a treatment strategy for neuroinflammation of Alzheimer's disease (AD). An IFN-FGF fusion protein (SEQ ID NO: 3) and a coding gene (SEQ ID NO: 4) of the IFN-FGF fusion protein are constructed, and the IFN-FGF fusion protein and the coding gene (SEQ ID NO: 4) are used for in-vitro pretreatment of OM-MSCs, so that the A-MS Cs-Exo exosome with anti-inflammatory and neuroprotective functions is obtained. In an A beta oligomer-induced AD neuroinflammation model, the A-MSCs-Exo significantly alleviates neuroinflammation and cognitive impairment by inhibiting excessive activation of hippocampal Iba1 + microglia cells, reducing serum IL-6 level, improving SOD activity and improving Morris water maze behavioral performance, the effect is better than that of traditional FGF-1 pretreatment (B-MSCs-Exo) and untreated exosome (C-MSCs-Exo), and the A-MSCs-Exo can be used for preparing the A beta oligomer-induced AD neuroinflammation model. The invention provides a novel exosome intervention strategy for AD treatment.

This invention provides the use of a biomarker in the preparation of a risk assessment product for mild cognitive impairment (MCI), wherein the biomarker includes Aβ oligomers. The Aβ oligomer biomarker alone has significant predictive value for MCI, achieving an area under the receiver operating characteristic (AUC) of 0.851 (95% confidence interval: 0.803–0.895) on the test set when distinguishing between cognitively normal and MCI subjects, demonstrating its superior performance in differentiating MCI subjects.

The invention discloses a novel immunosensor capable of realizing trace detection of A beta oligomer as well as a preparation method and application of the immunosensor. The preparation method of the immunosensor comprises the following steps: forming a gold nanoparticle-reduced graphene oxide composite layer; the gold nanoparticle-reduced graphene oxide composite layer is covered with cobalt-molybdenum disulfide composite suspension liquid to form a cobalt-molybdenum disulfide composite layer; covering the cobalt-molybdenum disulfide complex layer with an anti-A beta oligomer antibody solution to obtain an anti-A beta oligomer antibody layer; and covering bovine serum albumin on the anti-A beta oligomer antibody layer, and incubating for 30-60 minutes to obtain the immunosensor. According to test determination, the linear range of the immunosensor constructed by the invention is 1.11 * 10 <-9 > M to 1.11 * 10 <-14 > M, and the detection limit can be as low as 6.87 * 10 <-15 > M.

The present invention discloses a biosensor for detecting Alzheimer's disease markers, as well as a construction method and application thereof, relating to the field of biosensor technology. The construction method comprises the following steps: after cleaning a glassy carbon electrode, dripping a RuSi NPs@CS complex onto the surface of the cleaned glassy carbon electrode to obtain a RuSi NPs@CS / GCE electrode; immersing the RuSi NPs@CS / GCE electrode in a PHL:S double-strand solution for incubation to obtain the biosensor; the RuSi NPs@CS complex is obtained by mixing ruthenium silicon nanoparticles and chitosan; the PHL:S double-strand solution contains PHL chains activated by carboxyl groups and S chains through an incubation reaction. The biosensor has the advantages of high accuracy, strong sensitivity, and good selectivity, and can be used to accurately detect Aβ oligomers, a marker of Alzheimer's disease.

The invention discloses a preparation and quality control method of an A beta monomer. The method comprises the following steps: (1) mixing Abeta polypeptide with a buffer solution to obtain an Abeta polypeptide solution, and separating different components in the Abeta polypeptide solution according to the molecular weight of the polypeptide by using a molecular sieve method; (2) performing immunoblotting analysis on different components obtained in the step (1), and quantitatively analyzing the purity of an A beta monomer in each component by using an antibody for identifying the linear epitope of the A beta polypeptide; (3) testing and monitoring the aggregation kinetics result of the A beta monomer in each component by using sulfo-sulfoline T; and (4) according to the results of the step (2) and the step (3), carrying out quality control on the A beta monomer component. In order to better prepare the A beta monomer, the invention combines multiple protein purification and analysis technologies to solve the problem that A beta oligomer and truncated peptide are mixed in the A beta monomer, and provides a method for preparing the A beta monomer and controlling the quality of the A beta monomer.

The present invention discloses the use of a small molecule compound targeting Aβ oligomers in the preparation of a drug for alleviating or treating Alzheimer's disease, which can significantly improve the behavioral abnormalities of APP / PS1 mice. In particular, the compound PTO-29 can quickly penetrate the blood-brain barrier as a probe, and after binding to amyloid protein in the brain, it plays a good role in the early diagnosis of Alzheimer's disease; it has good safety after long-term administration, delays the progression of Alzheimer's disease and achieves a good therapeutic effect.

The present invention relates to the diagnostic use of highly toxic amyloid oligomers. In particular, the present invention relates to the use of the new highly toxic amyloid oligomer Aβo*3F as a target for the diagnosis of early and advanced Alzheimer's disease (AD) and AD-derived mild cognitive impairment (MCI), which is specifically bound by the 3F antibody, is present in the cerebrospinal fluid (CSF), blood and / or brain tissue of AD patients and AD-derived MCI patients and whose levels differ significantly in the CSF, blood and / or brain tissue of AD patients, MCI patients and healthy elderly, is a super-toxic oligomer, is the most dominant toxic component of the Aβ oligomer mixture and has a strong pathogenic effect, playing a key role in the development and progression of AD.

Inventors have shown evidence of VEGF accumulation in extracellular Aβ plaques in the post-mortem brain of patients with Alzheimer's disease (AD) and of the APP / PS1 mouse model of AD. They identified specific binding domains involved in the direct interaction between A0o and VEGF and engineered a peptide that blocks this interaction. The designed peptide binds to Aβ oligomers with high affinity and inhibits the process of Aβ self-aggregation, leading to the blockade of fibrillar aggregation. Furthermore, the peptide prevents soluble Aβ-derived toxins to target synapses in hippocampal neuron cultures and restores long-term potentiation in the hippocampus of the APP / PS1 mouse model of Alzheimer's disease. Thus, these findings have broad implications for preventing and treating diseases with Aβ neurotoxicity such as Alzheimer's disease. Accordingly, the invention relates to a peptide comprising the amino acid sequence KRKKSRYKSWSVYVG (SEQ ID NO: 1).

The present invention provides an antibody that binds to Aβ oligomers and its application, belonging to the field of medical technology. The antibody comprises: an L chain having CDR1, CDR2, and CDR3, wherein the amino acid sequence of the L chain of CDR1 is as shown in SEQ ID NO.1; the amino acid sequence of the L chain of CDR2 is as shown in SEQ ID NO.2; and the amino acid sequence of the L chain of CDR3 is as shown in SEQ ID NO.3; and an H chain having CDR1, CDR2, and CDR3, wherein the amino acid sequence of the H chain of CDR1 is as shown in SEQ ID NO.4; and the amino acid sequence of the H chain of CDR2 is as shown in SEQ ID NO.5. The present invention provides a monoclonal antibody that can bind to Aβ oligomers, as well as a method for preparing the monoclonal antibody and its application. Using the monoclonal antibody as a raw material and a unique repeating epitope sandwich method, Aβ oligomers can be detected with high specificity, high sensitivity, and high accuracy.

The present invention relates to an isoindol-sulfilimine compound and its preparation and its use as a sigma-2 receptor inhibitor. Compared with the prior art, the isoindol-sulfilimine compound prepared by the present invention can effectively inhibit the sigma-2 receptor activity by binding to the sigma-2 receptor and deformationally regulating the sigma-2 receptor complex, which will lead to the instability of the binding of adjacent Aβ oligomers to the receptor on the synapse, thus leading to the removal of Aβ oligomers from the synapse. It can be further used for the preparation of new therapeutic drugs for tumor and neurodegenerative diseases.