CN118217273B

CN118217273B - Application of NSC697923 in preparation of medicines for removing misfolded protein aggregates

Info

Publication number: CN118217273B
Application number: CN202410651857.3A
Authority: CN
Inventors: 殷鹏; 李晓江; 张晨; 王翔; 李世华; 欧凯丽; 贾青青; 侯珺淇; 朱龙洪
Original assignee: Jinan University
Current assignee: Jinan University
Filing date: 2024-05-24
Publication date: 2024-07-16
Anticipated expiration: 2044-05-24

Abstract

The invention discloses an application of NSC697923 in preparing a medicine for removing misfolded protein aggregates, and belongs to the technical field of medicines. According to the technical scheme, NSC697923 is applied to clearing of toxic protein aggregates of the cerebral nervous system for the first time, so that the level of misfolded protein aggregates in brains of AD mice and HD mice is effectively reduced, and genes which are abnormally expressed by the AD mice and the HD mice relative to healthy mice are obviously improved. Therefore, the UBE2N inhibitor NSC69792 is used for preparing the pharmaceutical composition of the neurodegenerative disease, lays a foundation for further drug development, and has potential treatment application prospects especially in the targeted treatment of Alzheimer's disease and Huntington's chorea.

Description

Application of NSC697923 in preparation of medicines for removing misfolded protein aggregates

Technical Field

The invention belongs to the technical field of medicines, and particularly relates to application of NSC697923 in preparation of a medicine for removing misfolded protein aggregates.

Background

Misfolding and aggregation of proteins is associated with a variety of neurodegenerative diseases, including the common Alzheimer's Disease (AD) and Huntington's Disease (HD). In these diseases, proteins and polypeptides may undergo misfolding under specific conditions, converting from a soluble native state to an insoluble amyloid aggregation state.

Alzheimer's disease is commonly called senile dementia, the onset is slow and difficult to find, the patient initially has hypomnesis, the judgment capability is gradually reduced, the language capability is gradually reduced, the space orientation capability of the patient is reduced along with the development of the disease, the emotion is gradually unstable, the daily life is difficult to self-care, the patient can seriously lose memory in the last stage, the behavior capability is seriously reduced, and finally the patient dies due to infection complications. AD is usually found in the elderly population, and Amyloid plaques, i.e. senile plaques, produced by aggregation of aβ (β -amylase) proteins are important pathological markers of AD by the age of onset of familial alzheimer's disease, which is more than 65 years old. The A beta protein is generated by sequentially shearing an amyloid precursor protein APP through beta-secretase and gamma-secretase. Because the beta sheet form of the aβ protein monomers makes them susceptible to aggregation, insoluble aβ protein aggregates are produced when the protein removal system is difficult to remove in time under multiple complications. The drug treatment of AD is mostly focused on related antibody drugs of Abeta, such as Ab Du Shan antibody, duonamab, and Lekanolamide mab; with the development of small molecule drugs including kinase inhibitors, such as hydrochlorofluorodrozine, masitinib and antiepileptic drugs NE3107, researchers gradually recognize that therapeutic approaches aimed at specific genes will have objective therapeutic prospects, for example, site-directed knockout of mutated APP alleles by CRISPR/Cas9 technology or reduction of β -secretase by knockout of BACE1 gene can achieve reduced aβ production.

Huntington's disease is an autosomal dominant inherited neurological degenerative disease, typical symptoms including chorea-like involuntary movements, cognitive disorders and psychotic behavior abnormalities. Huntington's disease is caused by abnormal amplification of the CAG repeat sequence of exon 1 of the (Htt) gene located on chromosome 4. When this CAG triplet is amplified (N > 35), it results in the amplification of the polyglutamine (polyQ) repeat sequence of the N-terminal region of huntingtin (Htt), and protein misfolding and aggregation. Although Htt is commonly expressed in the brain and in vivo, mutant Htt (mHtt) can lead to selective neurodegeneration, preferentially in the striatum, and spread to other brain areas as the disease progresses. Selective neurodegeneration in Huntington's disease is apparently associated with age-dependent accumulation of misfolded Htt in neuronal cells, which can lead to the formation of Htt protein aggregates in the brain, affecting intracellular transport and neuronal delivery. Since mHtt protein has a too complex pathological mechanism in cells, the currently known therapeutic drugs for HD are limited to treatment of disease support, such as treatment of chorea-like symptoms: deutetrabenazine, an ambrisentan tablet, is a novel vesicular monoamine transporter-2 (VMAT 2) inhibitor drug, and is a drug which can effectively control chorea symptoms after the deutetrabenazine; treatment of psychotic disorders: such as quetiapine, olanzapine or risperidone; treatment of cognitive disorders: the coenzyme Q10 and the immunomodulator and the like do not obtain the expected clinical effect, and achieve the specific treatment effect.

Although therapeutic drugs entering clinical trials of AD and HD continue to increase, it would be of greater significance and application value if therapeutic means could be developed based on the specific pathogenesis of neurodegenerative diseases that would radically eliminate misfolded protein aggregates in these two major degenerative diseases.

NSC697923 is a small molecule compound that was included in NCBI, molecular weight 267.26, and was screened for use as a specific inhibitor of UBE2N in 2013. Based on the current literature reports, the inhibitor is only used for inducing apoptosis of various tumor cells such as neuroblastoma cells, ovarian cancer, diffuse large B cell lymphoma cells and the like at the cellular level. To date, it has never been used for targeted treatment of neurodegenerative diseases, especially in animal model body for the clearance studies of misfolded proteins. Therefore, if the small molecule inhibitor NSC697923 can be used for the study of the clearance of the aggregate of neurodegenerative diseases such as Abeta and Htt, the small molecule inhibitor has more application value.

Disclosure of Invention

Aiming at the prior art, the invention provides the application of NSC697923 in preparing the medicines for removing misfolded protein aggregates, and provides a new technical scheme and research direction for treating neurodegenerative diseases.

In order to achieve the above purpose, the technical scheme adopted by the invention is that the application of NSC697923 in preparing a medicine for removing misfolded protein aggregates is provided, the medicine is a medicine for removing misfolded protein aggregates of patients with neurodegenerative diseases, and the structural formula of NSC697923 is as follows:

。

the beneficial effects of the invention are as follows: the UBE2N inhibitor NSC697923 is applied to the body in a known mode, so that the level of misfolded protein aggregates in neurodegenerative diseases can be effectively reduced, and the pharmaceutical composition has good treatment effect on the neurodegenerative diseases caused by the misfolded protein aggregates.

On the basis of the technical scheme, the invention can be improved as follows.

Further, misfolded protein aggregates in patients with neurodegenerative diseases are aβ protein aggregates.

Further, the neurodegenerative disease is Alzheimer's disease.

Further, misfolded protein aggregates in patients with neurodegenerative diseases are Htt protein aggregates.

Further, the neurodegenerative disease is huntington's disease.

The beneficial effects of the invention are as follows: according to the technical scheme, NSC697923 is applied to clearing of toxic protein aggregates in the cerebral nervous system for the first time, so that the level of misfolded protein aggregates in the brains of AD and HD mice is effectively reduced. Therefore, the UBE2N inhibitor NSC69792 can be used for preparing a pharmaceutical composition of neurodegenerative diseases, lays a foundation for further drug development, and has potential treatment application prospects especially in targeted treatment of Alzheimer's disease and Huntington's chorea.

Drawings

FIG. 1 shows Western blotting analysis results of hippocampal tissues of mice in the administration group and the control group at 4 weeks of the AD group, wherein the left side is the Western blotting analysis result of the beta-Amyloid 1-42 antibody specifically recognizing the Abeta aggregate and the monomer, and the right side is the Western blotting analysis result of the 6E10 antibody specifically recognizing the Abeta aggregate and the monomer;

FIG. 2 shows the results of immunoblotting analysis of Htt protein aggregates from mouse striatal tissue in the dosing group and the control group at 4 weeks of HD group;

FIG. 3 shows the results of immunofluorescence staining analysis of Abeta protein aggregates of hippocampal tissue of mice in the dosing group and the control group at 4 weeks of AD group (scale: 200 μm);

FIG. 4 shows the results of immunofluorescence staining analysis of Htt protein aggregates of striatal tissue in mice in the dosing group and the control group (scale: 200 μm) at 4 weeks in the HD group;

FIG. 5 shows the results of immunohistochemical staining analysis of Abeta protein aggregates in hippocampal tissue of mice in the dosing group at 4 weeks of AD group (scale: 200 μm);

FIG. 6 shows the results of immunohistochemical staining analysis of Htt protein aggregates of mouse striatal tissue in the dosing and control groups at 4 weeks in the HD group (scale: 200 μm);

FIG. 7 shows the results of a thermogram analysis of differential expressed genes in hippocampal tissue of mice at 4 weeks of AD group;

FIG. 8 shows the results of a thermal map analysis of differential expression genes in striatal tissue of mice at 4 weeks of HD group;

FIG. 9 is a cluster map of differentially expressed genes in hippocampal tissue of mice at 4 weeks of AD group;

FIG. 10 is a cluster map of differentially expressed genes in striatal tissue of mice at 4 weeks of HD group.

Detailed Description

The following describes the present invention in detail with reference to examples.

Example 1

12 5 Months old 5×FAD mice, 12 one year old HD mice, 12 one year old healthy mice, and the mouse strain was C57BL/6JGp.

The mice are divided into an AD group and an HD group, wherein the AD group is divided into 3 small groups of a slow-release pump administration group, a control group and a normal group; HD groups were 3 subgroups of i.p. administration, control and normal groups. Each group contained 6 mice, and the specific grouping and treatment methods are shown in Table 1.

TABLE 1 grouping and processing method for animal experiments

1. AD group

1.1 Sustained release pump injection administration

(1) The slow release pump was incubated at 37℃in an environment of 0.9% physiological saline.

(2) Diluting inhibitor NSC697923 (product number: HY-13811, brand: medChemExpress) with physiological saline to 20 μm concentration with 40% PEG300 as cosolvent, filling into slow release pump with 1.0 ml syringe and flat head filling needle, removing air bubbles in flow regulator, and connecting flow regulator with slow release pump; a spacer was installed on the flow regulator to give a regulator tube length of 2.0 mm.

(3) Placing the mice into an induction box, and performing induced anesthesia by using isoflurane, wherein the isoflurane percentage is 2.5% during induction, so that the mice are subjected to preoperative anesthesia; after the mice are completely anesthetized, the mice are placed on the foam-rubber cushion, the mouths of the mice are placed in the anesthetic mask, and the skull is fixed on the brain stereotactic instrument, so that the skull is ensured to be stable and bilaterally symmetrical. Adjusting the isoflurane percentage to 1.5% to maintain an anesthetic state, dipping a cotton swab in 75% alcohol to disinfect the skin of the head, the scalp, the shoulders and the neck of the mice; the scissors remove the hair on the top of the skull, cut off part of scalp and fascia under the scalp, dip a proper amount of 3% hydrogen peroxide with a cotton swab to digest the soft tissue on the surface of the skull until clear bregma is exposed. The anterior fontanel was drilled at 2.0 mm and the midline deviation 2.0 mm, and a flow regulator was implanted at a depth of 2.0 mm.

(4) Cutting skin of small part of shoulder and neck with scissors, separating subcutaneous connective tissue with hemostatic forceps, implanting slow release pump into subcutaneous space, inserting flow regulator needle vertically into the drill hole, fixing with dental cement, cutting top of regulator, and suturing incision with suture. The slow release pump flow rate was 0.13.+ -. 0.02. Mu.l/hr and total pump was about 100. Mu.l for 4 weeks.

1.2 Control group

The administration mode is consistent with that of the experimental group, wherein the administration content is 2% DMSO+40% PEG300+0.9% physiological saline, and the administration rate and the administration amount of the slow-release pump are consistent with those of the experimental group.

1.3 Normal group

The procedure was as for the 1.2 control group.

2. HD group

2.1 Intraperitoneal injection administration group

(1) Before the experiment, the articles used for injecting the mice are prepared, alcohol cotton balls and a syringe are prepared, and the syringe can be used for the next mouse only after being sterilized after being used, so that cross infection is avoided.

(2) Fixing mice: the mice are placed on a rearing cage, the middle part of the tail of the mice is lifted, the mice are slightly pulled backwards horizontally, the fur at the back of the neck of the mice is rapidly grasped, and the head of the mice is fixed so as to prevent the mice from being bitten. The tail of the mouse is fixed by the left ring finger or the little finger, so that the whole trunk of the mouse is fixed, the mouse is in a comfortable position, and if the trunk of the mouse cannot be kept vertical, the mouse can easily prick viscera to cause bleeding, and the experiment is affected.

(3) Injection: after grabbing the mice, the abdomen should be upward and the head should be in a low position. The right hand injector is inserted into the abdomen of the mouse, the injection part is 0.5 cm parts (which are parallel to the root of thigh) on both sides of the midline of the abdomen of the lower abdomen of the mouse, so as to avoid hurting viscera, the head of the mouse needs to be slightly tilted backwards when the mouse is ensured to be fixed, the needle is slowly inserted at about 45 degrees, the needle insertion depth is less than 1 cm, and the feeling of the needle insertion is the elimination of local skin depression and the feeling of falling. The injection solution was NSC697923 inhibitor, and 4 mg/kg of the injection was used as a cosolvent 40% PEG300 based on the weight of the mice, and the inhibitor stock solution was diluted to 200. Mu.l with 0.9% physiological saline. The dosing cycle was once every 1 day for 4 weeks.

(4) Drawing out the needle: to prevent leakage, the needle is rotated slightly and then pulled out slowly.

(5) After the injection, the mice were incubated, and after 5 minutes of observation, the mice were returned to the feeder cage with close attention to the state of the mice.

2.2 Control group

The administration mode is consistent with the experimental group, wherein the administration content is 2% DMSO+40% PEG300+0.9% physiological saline, and the administration frequency and the administration amount are consistent with the experimental group.

2.3 Normal group

The procedure was as for the 2.2 control group.

Experimental example

Taking the day of the beginning of the experiment as d0, observing the state of the mice every day, euthanizing the mice after the experiment period is finished, taking the brain tissues of the mice, and carrying out experiments such as western blot analysis detection, immunohistochemical staining detection, differential expression gene analysis and the like on the brain tissues of the mice.

The following are specific experimental procedures and results analysis.

Western blot analysis

1.1 Experimental procedure

(1) Placing a proper amount of fresh mouse protein tissue into a 1.5 ml centrifuge tube, adding RIPA cell lysate (10 mg/ml, containing protease inhibitor) and grinding beads, grinding three times in a frozen tissue grinder at-30deg.C under the conditions of 75 Hz and 30s, taking out the grinding beads, and placing the centrifuge tube on ice for 30 min;

(2) Performing ultrasonic disruption on tissue cells in the lysate by using an ultrasonic cell disruption instrument, wherein each tube is subjected to ultrasonic disruption for 3-5 times;

(3) Centrifuging the tissue lysate in a pre-cooled centrifuge at 4deg.C at a speed of 10000 rpm for 10: 10 min, transferring the supernatant to a new 1.5: 1.5 ml centrifuge tube;

(4) Preparing a reduced copper solution according to the requirements of the BCA protein concentration test kit in a ratio of 50:1; taking 2 μl of protein samples into a 96-well plate, adding 200 μl of reduced copper solution, and performing three repeated samples for each sample; taking 10 mu l of each 10-fold diluted protein standard sample, adding 200 mu l of reduced copper solution, and reacting at 37 ℃ for 25 min; detecting a light absorption value by an enzyme-labeled instrument, and calculating the concentration of the protein sample according to a standard curve equation;

(5) Mixing part of the sample with 5X SDS loading buffer, and regulating the protein concentration of each protein loading liquid to be 1 mug/mul; dry bath 10min at 98 deg.c, short centrifuging to collect condensate liquid from the pipe wall back into the pipe, and storing the prepared protein sample liquid in refrigerator at-80 deg.c;

(6) According to the size of the target protein, SDS-PAGE precast gel with the concentration of 4% -20% is selected, 1L electrophoresis buffer solution is prepared, and an electrophoresis tank is installed;

(7) Taking 15 μl of prepared protein sample loading liquid into the gel sample application hole, and carrying out protein electrophoresis at constant pressure of 80V;

(8) Preparing 1X membrane transfer liquid, installing a membrane transfer device, and transferring proteins onto a nitrocellulose NC membrane at a constant pressure of 100V and a constant pressure of 60 min;

(9) Preparing a sealing solution (5% skimmed milk), sealing at room temperature for 45 min%, washing residual skimmed milk on the membrane by using TBST, adding a primary antibody prepared from 3% BSA, and incubating on a shaker at 4 ℃ for 12-16 h;

(10) Recovering the first antibody, washing off residual antibody on the membrane by using TBST, preparing a corresponding second antibody in a ratio of 1:7000, and incubating at room temperature for 1 h;

(11) TBST washes off residual antibody on the membrane, mixes chemiluminescent solution in a 1:1 ratio, develops on a developing instrument and analyzes.

1.2 Analysis of results

Beta-Amyloid 1-42 and 6E10 are antibodies capable of specifically recognizing Abeta aggregates and monomers, and Western blot analysis was performed on AD mice administered for 4 weeks, and the results are shown in FIG. 1. As can be seen from fig. 1, the AD mice had reduced aβ protein monomers and aβ aggregates in their hippocampal tissues after administration of the sustained release pump injection inhibitor NSC697923 for 28 days, as compared to the control group.

MEM48 is an antibody capable of specifically recognizing Htt aggregate, and western blot analysis was performed on HD mice administered for 4 weeks, and the results are shown in fig. 2. As can be seen from fig. 2, the Htt protein aggregate level in the striatum of mice was reduced after the intraperitoneal injection of the inhibitor NSC697923, compared to the control group.

Immunofluorescent staining analysis

2.1 Experimental procedure

(1) The fresh dried slices or the slices which are restored to room temperature are dripped and washed by PBS and gently shaken for 5min times for 4 times;

(2) Triton-X100 at 0.3% concentration was immersed in the light shaking slice permeabilized with membrane 1 h;

(3) Dropwise washing with PBS for 2 times, slightly shaking and washing for 5 min times, washing for 4 times, and washing off membrane penetrating fluid; the hydrophobic pen circled around the tissue section, 3% BSA blocked 30 min;

(4) The primary antibody to be incubated is noted beside the tissue slice, 3% BSA is used for preparing the primary antibody, sealing solution is discarded, and shaking table incubation is carried out for 12-16 h at 4 ℃;

(5) Taking out the slices from the temperature of 4 ℃, rewarming to room temperature, washing with PBS (phosphate buffer solution) by dripping and shaking for 5 min times, and washing for 4 times; diluting the fluorescent secondary antibody with 1% BSA (1:1000) in a dark place, soaking all tissue slices in the secondary antibody solution, and gently shaking at room temperature for 1-2 h;

(6) Washing with PBS (phosphate buffer solution) for 4 times by shaking for 5min times; after washing off the fluorescent secondary antibody, dripping sudan black for dyeing for 30-60 s, immediately and thoroughly washing residual sudan black residues with 0.4% Triton X-100, and washing off 0.4% Triton X-100 with PBS;

(7) DAPI (1:1000) was diluted in PBS protected from light and counterstained at room temperature with light shaking for 10 min;

(8) Washing with PBS for 5min times, washing for 4 times, discarding PBS, and light-drying, and sealing with anti-quencher in dark place.

2.2 Analysis of results

The results of immunofluorescent staining analysis of hippocampal tissue of AD mice administered for 4 weeks using β -amyl 1-42 (green) and 6E10 (green) are shown in fig. 3. As can be seen from fig. 3, the slow-release pump-administered AD mice had reduced aβ protein aggregates in the CA2 and CA3 regions of the hippocampal tissue as compared to the control AD mice.

Immunofluorescent staining analysis was performed on brain striatum sections of HD mice administered for 4 weeks by using mEM (green), and the results are shown in fig. 4. As can be seen from fig. 4, the HD mice in the intraperitoneal injection administration group had reduced Htt aggregates compared to the HD mice in the control group.

Immunohistochemical staining analysis

3.1 Experimental procedure

(2) Soaking the tissue slice with 3% H ₂O₂ until no air bubbles appear on the slice, and washing with PBS for 5min times;

(3) Triton-X100 at 0.3% concentration was immersed in the light shaking slice permeabilized with membrane 1 h; washing with PBS (phosphate buffer solution) for 4 times by shaking for 5min times;

(4) The hydrophobic pen circles around the tissue section, and is blocked by 3% BSA+2% NGS+0.1% TritonX-100 PBS blocking solution, and is gently shaken at room temperature for 30 min;

(5) The primary antibody to be incubated is noted beside the tissue slice, the primary antibody is prepared by using a sealing liquid, the sealing liquid is discarded, and the tissue slice is incubated for 12-16 hours by a shaking table at 4 ℃;

(6) Taking out the slice, and washing the slice for 4 times after the slice is restored to room temperature and the PBS is dripped and washed by shaking for 5min times;

(7) Diluting the secondary antibody with PBS (3% BSA+0.1% TritonX-100), soaking all tissue sections in the secondary antibody solution, and gently shaking for 1 h; washing with PBS (phosphate buffer solution) for 4 times by shaking for 5min times;

(8) Streptavidin (strepavidin) labeled peroxidase and incubated at room temperature with gentle shaking for 10 min. Washing with PBS (phosphate buffer solution) for 4 times by dripping and shaking for 5min times; preparing a fresh DAB chromogen solution, staining immersed tissue sections until the immersed tissue sections are bright brown, and stopping the immersed tissue sections by PBS; washing with PBS (phosphate buffer solution) for 4 times by dripping and shaking for 5min times;

(9) Immersing the slices in 70%, 80%, 95%, 100% ethanol for dehydration of 5min in sequence, and then immersing in xylene twice, 5min each time;

(10) The tablets were blocked with neutral resin before xylene was dried out.

3.2 Analysis of results

AD mice given 4 weeks of dosing were subjected to immunohistochemical staining analysis and the results are shown in figure 5. As can be seen from fig. 5, the immunohistochemical staining results of AD group mice showed that the AD group AD mice administered with the slow release pump had a reduced level of aβ protein aggregates compared to the AD group mice administered with the control group.

Immunohistochemical staining analysis was performed on HD mice given 4 weeks of dosing, and the results are shown in fig. 6. As can be seen from fig. 6, the AD mice given by intraperitoneal injection had a reduced Htt aggregate level compared to the HD mice in the control group.

RNA sequencing (RNA-seq) analysis

4.1 Experimental procedure

(1) Putting 50-100 mg of mouse hippocampal tissue into a 1.5 ml sterile and enzyme-free centrifuge tube, adding TRIzol reagent 1 ml, grinding for about three times by a cryo-grinder at-30 ℃ under the conditions of 75Hz for 30s until no macroscopic tissue blocks exist in the tube, and standing at room temperature for 5 min;

(2) 200. Mu.l of chloroform was added to the tube, and the mixture was left to stand for 5min hours after thoroughly mixing; then centrifuging the mixture at the temperature of 4 ℃ at a rotating speed of 13000 Xg by a refrigerated centrifuge to obtain a mixture of min;

(3) Transferring the upper water phase into a new sterile and aseptic 1.5 ml centrifuge tube, adding 500 μl isopropanol, reversing, mixing thoroughly, and standing for 10: 10 min;

(4) Centrifuging at 13000 Xg at 4deg.C for 10 min; discarding the supernatant, taking 75% ethanol of 1ml to re-suspend the precipitate, centrifuging at the speed of 7500 Xg at 4 ℃ for 5 min again, discarding the supernatant, and drying the precipitated RNA for 5-10 min;

(5) Adding a proper amount of RNASE FREE water according to the precipitation volume of RNA, and enabling a water bath 15: 15 min of a centrifuge tube at 55 ℃ to promote RNA dissolution;

(6) Detecting RNA concentration with Nanodrop ultraviolet spectrophotometer, and freezing at-80deg.C.

4.2 Analysis of results

Differential expression gene analysis was performed on AD mice and HD mice administered for 4 weeks, respectively, and the results are shown in fig. 7 to 10. As can be seen from fig. 7 to 10, compared with the control group and the normal group mice, the RNA-seq thermogram analysis results show that the AD mice in the slow-release pump administration group and the HD mice in the intraperitoneal injection administration group, after the treatment with the inhibitor, cluster a gene (healthier mice) indicating significant up-regulation in the AD mice and the HD mice, and are significantly improved after the treatment with the inhibitor; clustering of two genes (healthier mice) indicating significant downregulation in AD mice and HD mice, improved significantly after inhibitor treatment; the enrichment factors of the multiple functional pathways are obviously down-regulated after treatment.

While specific embodiments of the invention have been described in detail in connection with the examples, it should not be construed as limiting the scope of protection of the patent. Various modifications and variations which may be made by those skilled in the art without the creative effort are within the scope of the patent described in the claims.

Claims

Use of NSC697923 in the manufacture of a medicament for the treatment of alzheimer's disease or huntington's disease, wherein the NSC697923 has the structural formula:

。
2. the use according to claim 1, wherein the drug for treating alzheimer's disease is a drug that eliminates aβ protein aggregates in alzheimer's disease patients.
3. The use according to claim 1, wherein the agent for treating huntington's disease is an agent that eliminates Htt protein aggregates in huntington's disease patients.