KR101717709B1 - Saikosaponin c as a regulator of preteins responsible for alzheimer's disease - Google Patents

Abstract

The present invention relates to psycho saponin c as a modulator of amyloid beta and tau protein, which are Alzheimer's dementia causing proteins, and provides a composition for the prevention and treatment of Alzheimer's dementia comprising psycho saponin c as an active ingredient. It is expected that the composition of the present invention can be used to prevent and treat Alzheimer's dementia more effectively.

Description

Saikosaponin C A A REGULATOR OF PRETEIN RESPONSIBLE FOR ALZHEIMER'S DISEASE as a modulator of Alzheimer '

The present invention relates to psychosaponin C (SSc) as a modulator of Alzheimer's Dementia causing protein.

Alzheimer's disease (AD) is a type of degenerative neurological disease and is known to be caused by two major causative proteins, amyloid beta (Aβ) and tau protein. Amyloid beta is a major component of senile plaques that accumulate outside the nerve cells of Alzheimer's dementia patients, and toxicity of amyloid beta to neurons is thought to be a major cause of Alzheimer's dementia (Hardy, JA and Higgins GA (1992) Alzheimer's disease: The amyloid cascade hypothesis. Science, 256, 184-185). In addition, tau protein is a major constituent of neurofibrillary tangles (NFTs) accumulated in nerve cells, and abnormal hyperphosphorylation of tau protein is also known to be the cause of Alzheimer's dementia. Alzheimer's Dementia is considered to be a malignant disease that does not progress to the onset of the onset and has no fundamental treatment. Therefore, it is necessary to study the development of a substance that is effective in alleviating or preventing disease progression.

Conventional patent technologies relating to psycho saponin c have been described in connection with nerve cell protection and regeneration, but are not explicitly associated with Alzheimer's dementia (US2011-0171389A1), not related to Alzheimer's dementia, Most of the patents (JP2002-145759) that have been developed as external medicine. The present invention relates to psycho saponin c, a natural substance showing a regulatory effect on a causative protein that is more directly related to Alzheimer's dementia, and its direct association with two major proteins of amyloid beta and tau protein in Alzheimer's disease , And can be used for the prevention and treatment of Alzheimer's dementia.

Disclosure of Invention Technical Problem [8] The present invention has been made to solve the above-mentioned conventional technical problems, and relates to psychosaponin c as a modulator of Alzheimer's dementia causing protein.

However, the technical problem to be solved by the present invention is not limited to the above-mentioned problems, and other matters not mentioned can be clearly understood by those skilled in the art from the following description.

Hereinafter, various embodiments described herein will be described with reference to the drawings. In the following description, for purposes of complete understanding of the present invention, various specific details are set forth, such as specific forms, compositions and processes, and the like. However, certain embodiments may be practiced without one or more of these specific details, or with other known methods and forms. In other instances, well-known processes and techniques of manufacture are not described in any detail, in order not to unnecessarily obscure the present invention. Reference throughout this specification to "one embodiment" or "embodiment" means that a particular feature, form, composition, or characteristic described in connection with the embodiment is included in at least one embodiment of the invention. Accordingly, the appearances of the phrase " in one embodiment "or" an embodiment "in various places throughout this specification are not necessarily indicative of the same embodiment of the present invention. In addition, the particular features, shapes, and compositions may be combined in any suitable manner in one or more embodiments.

Unless defined otherwise in the specification, all scientific and technical terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs.

In one embodiment of the present invention, the term "neurological disease" refers to a degenerative brain injury disease characterized by Alzheimer's disease, Parkinson's disease, epilepsy, stroke and ischemic brain disease, preferably Alzheimer's disease .

In one embodiment of the present invention, "psychosaponin" is extracted from a traditional Chinese herb radix bupleuri . Thirteen kinds such as psychosaponin a, psicosaponin b, psicosaponin c and psicosaponin d are isolated, . The composition of the present invention preferably employs psychosaponin c. It is reported that psycho saponin is used for skin aging inhibitor or cerebral nervous system disease and has an effect on neovascularization and regeneration of neurite. Saikosaponin regenerates the axons and dendrites of neurons to protect against damage to nerve cells and to stimulate growth and regeneration of nerve cells. Glutamate, an excitatory neurotransmitter, Induced neuronal death by inhibiting or delaying the death of neurons.

In one embodiment of the present invention, "psicosaponin c" means a compound of the following formula (1): for the purpose of the present invention, the psicosaponin c is a compound having an effect on the treatment of neurological diseases, preferably Alzheimer's dementia it means. The psycho saponin c of the present invention provides a pharmaceutical composition and a food composition for preventing and treating Alzheimer's disease, which comprises a pharmaceutically acceptable amount as an active ingredient.

Formula 1

In one embodiment of the present invention, "amyloid beta" is composed of 40 or 42 amino acids, and the amyloid precursor protein (APP) is cleaved by? -Secretase, Sequential cleavage cleaved by cryptase produces A [beta] peptides, and the resulting A [beta] peptides aggregate outside the nerve cells to form the elderly. A tendency to aggregate formation is in particular the Aβ _{1 -42} fragment consisting of 42 amino acids, which is due to two very hydrophobic amino acid residues at its C-terminus. The A [beta] _{i- 42} fragment is believed to have a high pathological potential, primarily responsible for and also responsible for the onset of neuropritic plaque formation in Alzheimer's dementia. In the beta used in the present invention is particularly preferably a _{1 -40} Aβ and Aβ _{1 -42.}

In one embodiment of the present invention, "tau protein" is a microtubule-associated protein (cytoskeleton protein). Tau protein is abundant in nerve cells of the central nervous system and plays an important role in the structural stabilization of nerve cells compared to other cells. Hyperphosphorylation of abnormal tau protein is a pathogenesis of Alzheimer's disease by accumulating NFT. In many studies, Alzheimer's disease is known to occur in the relationship between tau protein and GSK3β. GSK3β activates hyperphosphorylation of tau protein and results in nerve regeneration.

In one embodiment of the present invention, "prevention" means any action that inhibits gastrointestinal disease or delays development by administration of the composition.

In one embodiment of the present invention, "treatment" means any action that improves or alleviates symptoms due to gastrointestinal disease upon administration of the composition.

The term " pharmaceutically effective amount "in an embodiment of the present invention means an amount sufficient to treat a disease at a reasonable benefit / risk ratio applicable to medical treatment, and an effective dose level is determined by the kind and severity of the subject, , The type of gastrointestinal disorder, the activity of the drug, the sensitivity to the drug, the time of administration, the route of administration and rate of release, the duration of the treatment, factors including co-administered drugs, and other factors well known in the medical arts. The composition of the present invention may be administered as an individual therapeutic agent or in combination with other therapeutic agents, and may be administered sequentially or simultaneously with conventional therapeutic agents. And can be administered singly or multiply. It is important to take into account all of the above factors and to administer the amount in which the maximum effect can be obtained in a minimal amount without side effects, and can be easily determined by those skilled in the art.

&Quot; Pharmaceutical composition "in one embodiment of the present invention means a composition to be administered for a specific purpose. For the purpose of the present invention, the pharmaceutical composition of the present invention is used for improving or treating Alzheimer's dementia, and may comprise a composition for this and a pharmaceutically acceptable carrier, excipient or diluent. The pharmaceutical composition of the present invention varies depending on various factors including the activity of the specific compound used, age, weight, general health, sex, diet, time of administration, route of administration, rate of excretion, drug combination and the severity of the particular disease to be prevented or treated. And the dose of the pharmaceutical composition may be appropriately selected by a person skilled in the art depending on the condition of the patient, the body weight, the degree of disease, the type of drug, the route of administration and the period of time, and may be 0.0001 to 50 mg / kg or 0.001 to 50 mg / kg. The administration may be carried out once a day or divided into several times. The dose is not intended to limit the scope of the invention in any way. The pharmaceutical compositions according to the present invention can be formulated into pills, dragees, capsules, solutions, gels, syrups, slurries, suspensions. Examples of carriers, excipients and diluents that can be included in the pharmaceutical composition of the present invention include lactose, dextrose, sucrose, sorbitol, mannitol, xylitol, erythritol, maltitol, starch, acacia rubber, alginate, gelatin, calcium phosphate, calcium silicate , Cellulose, methylcellulose, microcrystalline cellulose, polyvinylpyrrolidone, water, methylhydroxybenzoate, propylhydroxybenzoate, talc, magnesium stearate and mineral oil.

In one embodiment of the present invention, the term "food composition" is used variously as a food composition for improving diseases. The food composition containing the composition of the present invention as an active ingredient may be used in various foods, , Tea, a vitamin complex, a powder, a granule, a tablet, a capsule, a confection, a rice cake, a bread and the like. The food composition of the present invention is composed of natural foods and their presentations which have little toxicity and side effects and can be safely used for prophylactic purposes even for long-term use. When the composition of the present invention is contained in the food composition, the amount thereof may be added in a proportion of 0.1 to 50% of the total weight. Here, when the food composition is prepared in a beverage form, there are no particular limitations other than those containing the food composition at the indicated ratios and may contain various flavors or natural carbohydrates such as ordinary beverages as an additional ingredient. That is, natural carbohydrates include monosaccharides such as glucose, disaccharides such as fructose, sucrose and the like and sugar sugars such as polysaccharide, dextrin and cyclodextrin, and sugar alcohols such as xylitol, sorbitol and erythritol can do. Examples of the flavors include natural flavors (such as tau martin, stevia extract (for example, rebaudioside A and glycyrrhizin), and synthetic flavors (for example, saccharin and aspartame). The food composition of the present invention can be used as a food composition containing various nutrients, vitamins, minerals (electrolytes), flavors such as synthetic flavors and natural flavors, colorants, pectic acid and its salts, alginic acid and its salts, Stabilizers, antiseptics, glycerin, alcohols, carbonating agents used in carbonated beverages, etc. These components may be used independently or in combination. The ratio of these additives is not so important, Is generally selected in the range of 0.1 to about 50 parts by weight per part.

In one embodiment of the present invention, there is provided a pharmaceutical composition for the treatment of neurological diseases, comprising C ₄₈ H ₇₈ O ₁₇ represented by the general formula (1) as an active ingredient. In this embodiment, the C ₄₈ H ₇₈ O ₁₇ has a molecular weight of 900-1000, wherein the C ₄₈ H ₇₈ O ₁₇ is a psychosaponin. Wherein said psycho saponin is psychosaponin c, wherein said neurological disease is selected from the group consisting of Alzheimer ' s dementia, Parkinson ' s disease, epilepsy, stroke and ischemic brain disease , Wherein said psychosaponin c provides a pharmaceutical composition targeting amyloid beta or tau protein, wherein in said embodiment, said neurological disease < RTI ID = 0.0 > The present invention provides a pharmaceutical composition characterized by being an Alzheimer ' s dementia.

In one embodiment of the present invention, there is provided a food composition for improving neurological diseases, comprising C ₄₈ H ₇₈ O ₁₇ represented by the general formula (1) as an active ingredient. In this embodiment, the C ₄₈ H ₇₈ O ₁₇ has a molecular weight of from 900 to 1000, and in this embodiment, the C ₄₈ H ₇₈ O ₁₇ is a psychosaponin. Wherein said psycho saponin is psycosaponin c, wherein said neurological disease is selected from the group consisting of Alzheimer ' s dementia, Parkinson ' s disease, epilepsy, stroke and ischemic brain disease , Wherein said psicosaponin c provides a food composition targeting amyloid beta or tau protein, wherein in said embodiment, said neurological disease < RTI ID = 0.0 > The present invention provides a food composition characterized by being Alzheimer ' s dementia.

Hereinafter, the present invention will be described in detail.

The present invention relates to psychosaponin c as a modulator of Alzheimer's dementia causing protein. It provides a composition for the prevention and treatment of Alzheimer's dementia comprising psycho saponin c as an active ingredient, and is effectively used for preventing and treating Alzheimer's dementia .

Figure 1 shows that the confirming that the most effective psycho saponin c of psycho saponin acting to inhibit Aβ and Aβ _{1 -40 1 -42} according to an embodiment of the present invention.
FIG. 2 shows the inhibitory effect of psicosaponin c on Aβ _{1 -40} secretion according to an embodiment of the present invention.
Figure 3 shows the inhibitory effect of psicosaponin c on A [beta] _{i- 42} secretion according to one embodiment of the present invention.
Fig. 4 shows that psycho saponin c inhibits the death of cerebral endothelial cells caused by A [beta] according to an embodiment of the present invention.
Figure 5 shows that psycho saponin c in accordance with one embodiment of the present invention attenuates abnormal tau phosphorylation.
Figure 6 shows that psycho saponin c promotes neurite outgrowth according to one embodiment of the present invention.
Figure 7 shows that psycho saponin c promotes assembly of microtubules according to one embodiment of the present invention.

Hereinafter, the present invention will be described in more detail with reference to Examples. It will be apparent to those skilled in the art that these embodiments are only for describing the present invention in more detail and that the scope of the present invention is not limited by these embodiments in accordance with the gist of the present invention .

Example  One: Psycho saponin  Preparation of c

Saikosaponin c was obtained from Nacalai Tesque (Kyoto, Japan) and dissolved in DMSO (Sigma Chemical Co., St. Louis, Mo.) to form a 10 mM stock solution and stored at -20 ° C until use. The concentration of psicosaponin c used in the present invention did not show any cytotoxic effect in any analyzed cell type. Wortmannin (WRT), GF-109203X (GFX), nerve growth factor (NGF) and paraformaldehyde (PFA) were purchased from Sigma. WRT and GFX were used to induce tau hyperphosphorylation in neuroblastoma cells. NGF was used to induce neurite outgrowth in PC12 cells. A colorimetric ELISA kit for amyloid beta protein analysis was purchased from Invitrogen (Carlsbad, Calif.). A beta-secretase activated fluorescence assay kit was purchased from Abcam (Cambridge, Mass.).

Example  2: Preparation of nerve cells

Example  2-1. Cell culture

Human neuroblastoma cell lines SH-SY5Y and SK-N-SH, human neuroglioma cell line H4, and rat chromosome-positive cell line PC12 were obtained from the American Type Culture Collection (ATCC) in the United States. Bovine microvascular endothelial cells (BMVEC) were obtained from Lonza (Walkersville, MD, USA). SH-SY5Y, SK-N-SH and H4 cells were cultured in high-glucose Dulbecco's modified Eagle's medium (DMEM) containing 10% FBS. PC12 cells were cultured in high-density-per-well DMEM containing 10% horse serum and 5% FBS. BMVEC was cultured in an endothelial basal medium containing several growth factors. The cells were cultured in a humidified 5% CO ₂ environment at 37 ° C.

Example  2-2. Preparation of primary mouse cortical neurons

Primary neuronal cell cultures were prepared from the cerebral cortices of C57BL / 6 mouse embryos on day 16 of embryo using enzymatic digestion by trypsin. For the Aβ secretion assay, high density cells (5 × 10 ⁶ cells) and low density cells (5 × 10 ⁵ cells) were placed in 6-well plates coated with poly-D lysine for neurite outgrowth analysis. The cultures were maintained in serum-free neurobasal medium containing 2% B-27 supplement (Invitrogen) to inhibit glia proliferation of glial proliferation. Cortical neurons were used for the analysis of Aβ secretion (1 week) and neurite outgrowth (3 days). Half of the medium was removed and replaced every other day with fresh medium.

Example  2-3. Mouse brain hippocampal slice culture ( Organotypic hippocampal  slice culture)

Mouse brain slices containing hippocampus were obtained from month-old C57BL / 6 mice. After the mouse is isoflurane anesthesia, the brain is quickly removed and the oxygen-saturated cold Krebs solution (126 mM NaCl, 2.5 mM KCl, 1.2 mM NaH ₂ PO ₄ .H ₂ O, 1.2 mM MgCl ₂ , 2.5 mM CaCl ₂ , it was placed in 11mM glucose and 25mM NaHCO _3, pH 7.4). Whole-brain coronal slices (260 microns thick) containing hippocampal cross-sections were prepared using a Leica VT1200 (Buffalo Grove, IL, USA). The slices were cultured in 6-well culture plates in an organic trait Millicell cell culture insert (Millipore, Billerica, MA, USA).

All animal tests were performed according to the guidelines of the Institutional Animal Experimental Ethics Committee (IACUC) of Yonsei University College of Medicine and Beth Israel Deaconess Medical Center

Example  3: Psycho saponin  Identification and analysis of c

Example  3-1. Cohesion Aβ _{25 -35} Preparation of

In Synthetic _{Aβ 25 -35 (Sigma, St. Louis} , MO, USA) a sterile physiological saline, pH 7.4 to a final concentration of 100μM was solubilized (solubilized). When preparing the aggregated A [beta] peptide, the A [beta] _25-35 solution was incubated at 37 [deg.] C for 7 days. It was treated with an Aβ BMVEC to _{25 -35} for the cytotoxicity assay

Example  3-2. Aβ  Quantification of secretion

Aβ levels secreted in the medium were _measured using mouse Aβ _{1 -40} , human Aβ _{1 -40} and human Aβ _{1 -42} colorimetric sandwich ELISA kits (Invitrogen) according to the manufacturer's instructions. Samples and standards diluted 1: 2 to 1: 5 with the dilution buffer provided in the kit were incubated with Aβ C-terminal specific biotinylate rabbit detection antibody on plates coated with Aβ N-terminal specific monoclonal capture antibody Respectively. Samples and standards were incubated for 3 hours at room temperature for binding with A [beta] capture and detection antibodies. After washing four times, the Aβ antibody immobilized on the sample or the standard was incubated with horseradish peroxidase-labeled streptavidin for 30 minutes. A colorless substrate, 3,3 ', 5,5'-tetramethylbenzidine (TMB), which produces color directly proportional to the amount of Aβ in the sample, was added and reacted. The reaction was terminated using a stop solution and measured at 450 nm optical density using a plate reader. Aβ _1-40 and Aβ _{1 -42} concentrations were re-calculated using the standard curve by comparing the absorbance with the absorbance of the sample and the standard are shown as a percentage of the control results (Fig. 2 and 3).

Example  3-3. beta- Three Cretaceous  Fluorescence detection of active

The effect of psychosaponin c on beta-secretase activity was analyzed using the fluorescent beta-secretase activity assay kit (Abcam) according to the given protocol. After the cells were dissolved in the extraction buffer, the supernatant was collected and the protein concentration was determined using BCA protein assay. The supernatant was incubated in the dark at 37 [deg.] C with a beta-secretase substrate and reaction buffer (both supplied with the kit). After one hour incubation, fluorescence excitation and emission wavelengths were measured at 335-355 and 495-510 nm, respectively. The beta-secretase activity is expressed in relative fluorescence units (RFU) per μg protein sample.

Example  3-4. Apoptosis assay

After treatment with 10 μM Aβ _{25 -35} in the presence or absence of various concentrations of psychosaponin c for 72 hours, the BMVEC cell death rate was determined using the Trypan blue staining method. Viable cells were determined based on the ability to exclude the dye. The cell death rate according to psycho saponin c is shown in Fig.

Example  3-5. sub-G1 Fraction Flow cell  Analytical detection

10μM Aβ sikyeotgo stained for _{25 -35} 60 hours after the treatment in the psycho saponin c presence or absence of various concentrations, the cell DNA with propidium iodide (propidium iodide (PI), Sigma ) FACScan flow cytometer (Becton Dickinson, Franklin Lakes, NJ) to quantify the sub-G1 fraction. After fixation with cold 70% ethanol, the cells were washed twice with PBS and stained for 30 minutes in the dark at room temperature using 50 μg / ml PI. 10,000 cells per sample were analyzed using Cell Quest Pro software (Becton Dickinson) (Figure 4).

Example  3-6. Phosphatidylserine  Expression Flow cell  Analytical detection

Cells were harvested after treatment with 10 μM Aβ _{25 -35} for 48 h in the presence or absence of psychocaponin c at various concentrations. Cells at the stage of death were detected using the Aannexin V-FITC apoptosis detection kit (BioVision, Mountain View, Calif.). Cells were stained with PI and annexin-V for 10 min in the dark at room temperature and then analyzed using a flow cytometer (Becton Dickinson). PI and annexin V were detected in the FL-2 and FL-1 channels, respectively. Data on 10,000 cells were recorded in a logarithmic scale in an enumerated manner. Data analysis was performed using Cell Quest Pro software (BD Biosciences). Annexin V-positive cells were defined as death-progressing stage cells (Fig. 4).

Example  3-7. Immunoblot  analysis

Immunoblotting was performed to observe phosphorylation of tau protein (Figure 5) and tubulin polymerization (Figure 7). Cells were treated with lysis buffer [50 mM Tris-HCl (pH 7.4), 150 mM NaCl, 1 mM EDTA, 1% protease inhibitor cocktail (Sigma) and phosphatase inhibitor cocktail (Sigma) Solubilization was carried out using Triton X-100, 1% sodium dioxyclicate, 0.1% SDS, 1 mM DTT and the soluble protein concentration was determined using Bradford assay (Bio-Rad Laboratories, Hercules, CA) Samples (10 μg / lane) were separated by SDS-polyacrylamide gel electrophoresis (SDS-PAGE) and transferred to PVDF membranes (NEN, PerkinElmer, Wellesley, MA) (Invitrogen, Carlsbad, Calif., USA) and PHF-13 (p-Ser396-Tau) Tau) (Anaspec, Fremont, CA, USA) Primary antibodies were detected using a horseradish peroxidase-conjugated secondary antibody and We stern Lightning Plus-ECL (Perkin Elmer) chemiluminescence system.

Example  3-8. Neurite outgrowth quantification analysis

To induce differentiation, PC12 cells were placed in serum-free conditions (0.5% horse serum and 0.25% FBS) in poly-L-lysine (Sigma) coated 6-well plates and incubated with 50 ng / Treated in the presence or absence of saponin c. After induction of differentiation, cells were grown into neurites and fixed with 4% PFA for 10 minutes at room temperature. The level of neurite outgrowth was quantified by determining the percentage of differentiated cells and measuring the mean neurite length per differentiated cell. In order to increase the reliability and reproducibility of the experiment, three independent experiments were performed and 10 images were selected randomly for each experiment. Differentiation of cells was defined as having at least one neurite having a length of more than a cell body diameter.

Example  3-9. Tubulin  Polymerization method

PC12 cells treated with psycho saponin c for 24 hours were harvested and incubated in a hypotonic buffer (1 mM MgCl ₂ , 2 mM EGTA, 0.5% NP-40, 20 mM Tris-HCl (pH 6.8)) for 5 minutes at 37 ° C Lt; / RTI > The cell lysate was centrifuged at 18,000 x g for 10 minutes at < RTI ID = 0.0 > 25 C. < / RTI > The supernatant containing un polymerized (soluble) tubulin was transferred to a new tube. The pellet containing polymerized (unavailable) tubulin was resuspended in the same volume of storage buffer and sonicated for 10 minutes on / off pulse for 2 minutes. Protein samples (5 μg / lane) of the two fractions were separated by SDS-PAGE. The amount of tubulin expression was quantitated by density measurement and analyzed using ImageQuant software (FIG. 7).

Statistical analysis

Statistical analysis was performed using SAS 8.1 statistical analysis software (SAS Institute, Inc., Cary, NC). All experiments were repeated three times and the results were expressed as mean ± standard error. The data were analyzed by Dunnett multiple post hoc Were evaluated using the analytical method. Statistical significance was considered significant if the significance level P was less than 0.05, and statistically significant if the P value was less than 0.01.

Claims (14)

A pharmaceutical composition for the treatment of neurological diseases, which comprises C ₄₈ H ₇₈ O ₁₇ represented by the following formula (1) as an active ingredient,
Wherein said neurological disease is at least one selected from the group consisting of Alzheimer's Dementia, Parkinson's disease, epilepsy, stroke and ischemic brain disease.
Formula 1

The method according to claim 1,
Wherein the C ₄₈ H ₇₈ O ₁₇ has a molecular weight of 927.12. The method according to claim 1,
Wherein said C ₄₈ H ₇₈ O ₁₇ is psychosaponin c. delete delete The method of claim 3,
Wherein said psychosaponin c targets amyloid beta or tau protein. The method according to claim 1,
Wherein said neurological disease is Alzheimer ' s dementia. CLAIMS 1. A food composition for improving neurological diseases comprising C ₄₈ H ₇₈ O ₁₇ represented by the following formula (1) as an active ingredient:
Wherein the neurological disease is at least one selected from the group consisting of Alzheimer's Dementia, Parkinson's disease, epilepsy, stroke and ischemic brain disease.
Formula 1

9. The method of claim 8,
Wherein the C ₄₈ H ₇₈ O ₁₇ has a molecular weight of 927.12. 9. The method of claim 8,
Wherein the C ₄₈ H ₇₈ O ₁₇ is psicosaponin c. delete delete 11. The method of claim 10,
Wherein said psychosaponin c is targeted to amyloid beta or tau protein. 9. The method of claim 8,
Wherein the neurological disease is Alzheimer ' s dementia.

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