CN110200998B - Preparation of neuron-derived exosome and application of neuron-derived exosome in treating senile dementia - Google Patents
Preparation of neuron-derived exosome and application of neuron-derived exosome in treating senile dementia Download PDFInfo
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- A61K35/00—Medicinal preparations containing materials or reaction products thereof with undetermined constitution
- A61K35/12—Materials from mammals; Compositions comprising non-specified tissues or cells; Compositions comprising non-embryonic stem cells; Genetically modified cells
- A61K35/30—Nerves; Brain; Eyes; Corneal cells; Cerebrospinal fluid; Neuronal stem cells; Neuronal precursor cells; Glial cells; Oligodendrocytes; Schwann cells; Astroglia; Astrocytes; Choroid plexus; Spinal cord tissue
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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
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- C12N5/00—Undifferentiated human, animal or plant cells, e.g. cell lines; Tissues; Cultivation or maintenance thereof; Culture media therefor
- C12N5/06—Animal cells or tissues; Human cells or tissues
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- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
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- G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
- G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
- G01N33/68—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving proteins, peptides or amino acids
- G01N33/6893—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving proteins, peptides or amino acids related to diseases not provided for elsewhere
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- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N2800/00—Detection or diagnosis of diseases
- G01N2800/28—Neurological disorders
- G01N2800/2814—Dementia; Cognitive disorders
- G01N2800/2821—Alzheimer
Abstract
Preparation of neuron-derived exosome and application thereof in treating senile dementia. The invention provides application of neuron-derived exosomes in preparation of a medicament, wherein the medicament is used for treating senile dementia. The exosome from the neuron can promote the degradation and the clearance of beta-amyloid protein, effectively improve the pathological phenotype of senile dementia and has great application prospect.
Description
Technical Field
The invention relates to the field of biomedicine. In particular to preparation of a neuron-derived exosome and application thereof in treating senile dementia.
Background
Exosomes (exosomes) are extracellular vesicles with a diameter of about 30-150nm, and are generated by fusing multi-vesicular bodies (MVBs) and plasma membranes and released into extracellular spaces. Almost all types of cells in vitro and in vivo, including cells in the central nervous system, can secrete exosomes under physiological or pathological conditions. To date, people have separated them from various body fluids such as blood, cerebrospinal fluid and urine. Exosomes from different cells contain complex and different proteins, miRNAs and other substances, so that the exosomes can directly act on physiological and pathological functions such as receptor cells, substance transport among cells, signal transduction and the like.
Senile dementia is a progressive degenerative disease of the nervous system with hidden diseases, and Alzheimer's Disease (AD) is a kind of senile dementia, and the pathological features of the senile dementia are senile plaques formed by abnormal aggregation of beta-Amyloid (beta-Amyloid, Abeta) in the extracellular space and neuro-tangles formed by over-phosphorylation of Tau protein in the intracellular space.
At present, the relationship between exosomes and senile dementia remains to be studied intensively.
Disclosure of Invention
The present invention aims to solve at least to some extent at least one of the technical problems of the prior art.
It should be noted that the present invention has been completed based on the following findings of the inventors:
at present, studies have reported that almost all types of cells in vivo and in vitro, including cells in the central nervous system, can secrete exosomes under physiological or pathological conditions. Exosomes from different cells contain complex and different miRNAs, proteins and the like, and their effects vary, and exosomes from all sources may not play a positive role in the treatment of alzheimer's disease. The inventor finds that the exosome derived from the neuron can effectively play a role in treating the senile dementia by promoting the degradation and clearance of the A beta protein. In addition, the exosome from the neuron is convenient to obtain, and the application prospect is great.
To this end, in one aspect of the invention, the invention proposes the use of a neuron-derived exosome for the preparation of a medicament. According to an embodiment of the invention, the medicament is for the treatment of senile dementia. The inventor finds that the exosome from the neuron can treat the senile dementia and has a high application prospect.
According to an embodiment of the present invention, the use of said neuron-derived exosomes for the preparation of a medicament may also have the following additional technical features:
according to embodiments of the invention, the exosomes may promote degradation and clearance of a β protein.
According to an embodiment of the invention, said exosomes are derived from hippocampal neuronal cells or cerebellar neuronal cells, preferably cerebellar neuronal cells.
In yet another aspect of the invention, the invention features a method of obtaining a neuron-derived exosome. According to an embodiment of the invention, the method includes, but is not limited to: (1) carrying out cell culture on the neuron cells, and collecting supernatant; and (2) isolating exosomes from the supernatant. Therefore, the neuron-derived exosome obtained by the method provided by the embodiment of the invention has the advantages of high activity, high yield and simplicity and convenience in operation, and is suitable for large-scale application.
According to an embodiment of the present invention, the neuronal cells are derived from hippocampal neuronal cells or cerebellar neuronal cells, preferably cerebellar neuronal cells.
According to the embodiment of the invention, the culture medium adopted by the cell culture is Neurobasal culture medium containing penicillin, streptomycin and B27 serum-free additive.
According to an embodiment of the present invention, step (2) further includes, but is not limited to: and (3) carrying out ultrafiltration concentration on the supernatant, enabling the obtained concentrated solution to flow through a qEV small column, eluting by using a PBS buffer solution, discarding the first 1-2 mL of eluent, and collecting the subsequent 1.5-2.5 mL of eluent so as to obtain the exosome.
In yet another aspect of the present invention, the present invention provides a method for screening a drug for treating senile dementia. According to an embodiment of the invention, the method includes, but is not limited to: administering a candidate drug to brain tissue of an animal suffering from senile dementia as an experimental group, while brain tissue of the animal not administered serves as a control group; respectively measuring the levels of Abeta protein in the brain tissues of an experimental group and a control group, and determining whether the candidate medicine is used for treating the senile dementia; wherein, the medicament for treating the senile dementia contains exosome derived from neuron. Therefore, the method provided by the embodiment of the invention can be used for effectively screening out the medicine for treating the senile dementia.
According to an embodiment of the present invention, a level of a β protein in brain tissue of the experimental group of animals that is lower than a level of a β protein in brain tissue of the control group of animals is an indication that the drug candidate is a drug for treating senile dementia.
Additional aspects and advantages of the invention will be set forth in part in the description which follows and, in part, will be obvious from the description, or may be learned by practice of the invention.
Drawings
The above and/or additional aspects and advantages of the present invention will become apparent and readily appreciated from the following description of the embodiments, taken in conjunction with the accompanying drawings of which:
FIG. 1 shows a transmission electron micrograph of exosomes according to one embodiment of the invention, wherein the magnification is 200000%;
figure 2 shows a NanoSight measured diameter profile of exosomes according to one embodiment of the invention.
Detailed Description
The following describes embodiments of the present invention in detail. The following examples are illustrative only and are not to be construed as limiting the invention.
It should be noted that the terms "first" and "second" are used for descriptive purposes only and are not to be construed as indicating or implying relative importance or implicitly indicating the number of technical features indicated. Thus, a feature defined as "first" or "second" may explicitly or implicitly include one or more of that feature. Further, in the description of the present invention, "a plurality" means two or more unless otherwise specified.
The invention provides application of neuron-derived exosomes in preparation of medicines, a method for obtaining the neuron-derived exosomes and a method for screening medicines for treating senile dementia, which are respectively described in detail below.
Application of neuron-derived exosome in preparation of medicine
In one aspect of the invention, the invention provides the use of a neuron-derived exosome in the preparation of a medicament. According to an embodiment of the invention, the medicament is for the treatment of senile dementia. The inventor finds that the exosome from the neuron can treat the senile dementia and has a high application prospect.
According to embodiments of the invention, exosomes may promote degradation and clearance of a β proteins. The inventor finds that the neuron-derived exosome can promote the degradation of the A beta protein and remove the A beta protein, thereby playing a role in treating the senile dementia.
According to an embodiment of the invention, the exosomes are derived from hippocampal neuronal cells or cerebellar neuronal cells. The inventor finds that the exosome derived from the hippocampal neuron cell or the cerebellum neuron cell can promote the degradation and clearance of the A beta protein, thereby playing a role in treating the senile dementia, wherein the exosome derived from the cerebellum neuron cell has better effect.
The term "treatment" as used herein is intended to mean obtaining a desired pharmacological and/or physiological effect. The effect may be prophylactic in terms of complete or partial prevention of the disease or symptoms thereof, and/or may be therapeutic in terms of a partial or complete cure for the disease and/or adverse effects resulting from the disease. As used herein, "treatment" encompasses diseases in mammals, particularly humans, including: (a) preventing disease (e.g., preventing Alzheimer's disease) or the occurrence of a condition in an individual who is susceptible to the disease but has not yet been diagnosed with the disease; (b) inhibiting a disease, e.g., arresting disease progression; or (c) alleviating the disease, e.g., alleviating symptoms associated with the disease. As used herein, "treatment" encompasses any administration of a drug or compound to an individual to treat, cure, alleviate, ameliorate, reduce, or inhibit a disease in the individual, including, but not limited to, administering a drug containing neuron-derived exosomes as described herein to an individual in need thereof.
Method for obtaining neuron-derived exosomes
In yet another aspect of the invention, the invention features a method of obtaining a neuron-derived exosome. According to embodiments of the present invention, methods include, but are not limited to: (1) carrying out cell culture on the neuron cells, and collecting supernatant; and (2) separating the exosome from the supernatant to obtain the exosome. Therefore, the exosome obtained by the method for obtaining the neuron-derived exosome according to the embodiment of the invention has the advantages of strong activity, high yield, simple and convenient operation and suitability for large-scale application.
According to an embodiment of the present invention, the neuronal cells are derived from hippocampal neuronal cells or cerebellar neuronal cells. The inventor finds that the exosome derived from the hippocampal neuron cell or the cerebellum neuron cell can promote the degradation and clearance of the A beta protein, thereby playing a role in treating the senile dementia, wherein the exosome derived from the cerebellum neuron cell has better effect.
According to the embodiment of the invention, the culture medium used for cell culture is Neurobasal medium containing penicillin, streptomycin and B27 serum-free additive. Therefore, the activity of the cultured exosome is high.
According to an embodiment of the present invention, step (2) further includes, but is not limited to: and (3) carrying out ultrafiltration concentration on the supernatant, enabling the obtained concentrated solution to flow through a qEV small column, eluting by using a PBS buffer solution, discarding the first 1-2 mL of eluent, and collecting the subsequent 1.5-2.5 mL of eluent so as to obtain the exosome. Therefore, the obtained exosome has high purity and good activity.
Method for screening drug for treating Alzheimer's disease
In yet another aspect of the present invention, the present invention provides a method for screening a drug for treating senile dementia. According to an embodiment of the invention, the method includes, but is not limited to: the candidate drug is administrated to the brain tissue of the animal suffering from the senile dementia as an experimental group, and meanwhile, the brain tissue of the animal without the candidate drug is taken as a control group; respectively measuring the levels of Abeta protein in the brain tissues of an experimental group and a control group, and determining whether the candidate medicine is used for treating the senile dementia; wherein, the medicament for treating the senile dementia contains exosomes from neuron sources. As described above, the inventors found that exosomes derived from neurons can promote degradation and clearance of a β protein, and therefore, brain tissue cells to which a drug candidate was applied were used as an experimental group, while brain tissue cells to which the drug candidate was not applied were used as a control group. After a period of administration, the levels of a β protein in brain tissue cells of the experimental group and the control group are measured, and if the level of a β protein in the experimental group is decreased compared to the level of a β protein in the control group, it indicates that the candidate drug contains exosomes derived from neurons, which is the target drug. Therefore, the method provided by the embodiment of the invention can be used for effectively screening out the medicine for treating the senile dementia.
According to the embodiment of the invention, the level of the A beta protein in the brain tissue of the experimental group of animals is lower than the level of the A beta protein in the brain tissue of the control group of animals, which is an indication that the candidate drug is a drug for treating senile dementia. As described above, neuron-derived exosomes can promote degradation and clearance of a β protein, and therefore, if the level of a β protein in the experimental group is reduced compared with that in the control group, it indicates that the candidate drug contains neuron-derived exosomes, i.e., the target drug.
It will be appreciated by those skilled in the art that the features and advantages described above in relation to the use of exosomes of neuronal origin in the preparation of a medicament are equally applicable to the method of screening for a medicament for the treatment of senile dementia and will not be described in further detail herein.
The scheme of the invention will be explained with reference to the examples. It will be appreciated by those skilled in the art that the following examples are illustrative of the invention only and should not be taken as limiting the scope of the invention. The examples, where specific techniques or conditions are not indicated, are to be construed according to the techniques or conditions described in the literature in the art or according to the product specifications. The reagents or instruments used are not indicated by the manufacturer, and are all conventional products commercially available.
Example 1
1. Cerebellum primary neuron culture
The cerebellum primary neurons were cultured in Neurobasal medium (containing 2% B27, 0.5mmol/L L-Gln, 1% 100. mu.g/mL penicillin and 100. mu.g/mL streptomycin) and cell culture supernatants were collected.
2. Separation and extraction of exosomes
The collected culture supernatant of neuronal cells was concentrated by ultrafiltration, and the culture supernatant was concentrated by ultrafiltration. Referring to qEV molecular exclusion chromatography (SEC) small column specification, vesicle with particle size of 40-150nm is obtained, namely neuron-derived exosome, and finally 1.5mL PBS eluate for collecting corresponding components is placed in 1.5mL EP tube and stored at-80 ℃ for later use.
3. Identification of exosomes
The appearance of the exosome is observed by a transmission electron microscope, and the result is shown in figure 1, the exosome obtained by the experimental group is a small body with a uniform appearance, a diameter slightly smaller than the diameter of the small body and a teacup saucer-like structure with a clear film, and the appearance of the exosome is a typical appearance of the transmission electron microscope.
The molecular diameter of the obtained exosome is measured by adopting NanoSigt, and the result is shown in figure 2, and the obtained exosome molecular diameter is between 30 and 150nm and accords with the molecular diameter range of the exosome.
4. Research on neuron-derived exosome for improving senile dementia
8-month-old APP/PS1 transgenic mice (AD mice) with the genetic background of C57BL/6J are selected, neuron-derived exosome injection is carried out by referring to a standard map through a brain stereotaxic instrument (the right ventricle injection positioning parameters of the mice are 0.8mm behind bregma, 2.5mm under dura and 0.8mm aside). The injection time for each animal was 5 minutes and the needle was left for 10 minutes.
After 7 days of injection, Morris water maze experiments are carried out, including two parts of learning training experiments and positioning navigation experiments. And operating the computer, setting parameters and then carrying out the experiment. The time for the mouse to reach the safe platform in the pool (latency) was recorded in the learning training (first 6 days); and (5) removing the platform in the positioning navigation test by the 7 th day, and recording the time of the mouse continuously swimming in the quadrant where the original platform is located, the times of passing through the quadrant where the original platform is located and the times of the position where the original platform is located. The results are shown in tables 1 and 2.
TABLE 1 incubation period for daily learning training experiments in groups of mice
**P<0.05，*P<0.01, AD-control vs AD-exosomes
TABLE 2 day 7 mice positioning navigation experiment
**P<0.05，*P<0.01, AD-control vs AD-exosomes
Brain tissue was taken after the water maze experiment and the protein levels of a β in the brain and cerebellum were determined. The results are shown in Table 3.
TABLE 3 concentration of A.beta.protein in different brain regions of various groups of mice
| Mean±SE | Cerebrum (pg/mL) | Cerebellum (pg/mL) |
| AD-control | 66.1±13.5 | 10.1±4.4 |
| AD-exosomes | 49.8±11.3* | 9.8±2 |
*P<0.05, AD-control vs AD-exosomes
The results show that the neuron-derived exosome can obviously improve the learning cognitive ability of the senile dementia mouse, obviously reduce the A beta protein level in the brain tissue of the senile dementia mouse and achieve the effect of effectively improving the pathological phenotype of the senile dementia mouse.
In the description herein, references to the description of the term "one embodiment," "some embodiments," "an example," "a specific example," or "some examples," etc., mean that a particular feature, structure, material, or characteristic described in connection with the embodiment or example is included in at least one embodiment or example of the invention. In this specification, the schematic representations of the terms used above are not necessarily intended to refer to the same embodiment or example. Furthermore, the particular features, structures, materials, or characteristics described may be combined in any suitable manner in any one or more embodiments or examples. Furthermore, various embodiments or examples and features of different embodiments or examples described in this specification can be combined and combined by one skilled in the art without contradiction.
Although embodiments of the present invention have been shown and described above, it is understood that the above embodiments are exemplary and should not be construed as limiting the present invention, and that variations, modifications, substitutions and alterations can be made to the above embodiments by those of ordinary skill in the art within the scope of the present invention.
Claims (1)
1. Use of a neuron-derived exosome in the preparation of a medicament, characterized in that the medicament is for the treatment of alzheimer's disease;
the exosome can promote the degradation and elimination of the Abeta protein;
the exosomes are derived from cerebellar neuronal cells.
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