CN119818652A - Pharmaceutical composition for preventing/treating Alzheimer's disease - Google Patents
Pharmaceutical composition for preventing/treating Alzheimer's disease Download PDFInfo
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- CN119818652A CN119818652A CN202510317887.5A CN202510317887A CN119818652A CN 119818652 A CN119818652 A CN 119818652A CN 202510317887 A CN202510317887 A CN 202510317887A CN 119818652 A CN119818652 A CN 119818652A
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Description
Technical Field
The invention belongs to the technical field of biological medicines, and particularly relates to a pharmaceutical composition for preventing and/or treating Alzheimer's disease.
Background
Alzheimer's Disease (AD) is a chronic neurodegenerative Disease that mainly affects the cognitive function of the elderly, one of the most common types of dementia, and is mainly manifested by memory loss, decline in cognitive function and altered behavior. The etiology of Alzheimer's disease is complex, involves the co-action of genetic and environmental factors, and its pathogenesis is not completely understood, but is widely believed to be closely related to multiple pathological processes such as beta-amyloid (Abeta) deposition, neurofibrillary tangles (NFTs), neuronal synaptic dysfunction, metabolic abnormality, neuroinflammation and oxidative stress. Among them, overproduction and clearance of β -amyloid (aβ) leads to its deposition in the cerebral cortex and hippocampus to form plaques, leading to neuronal dysfunction （Teeba Athar, K. Al Balushi et al. "Recent advances on drug development and emerging therapeutic agents for Alzheimer's disease." Molecular Biology Reports(2021).）. neurofibrillary tangles (NFTs) caused by abnormally phosphorylated Tau protein aggregation, which is hyperphosphorylated in the brain of AD patients, resulting in its loss of ability to bind to microtubules, thereby disrupting microtubule structure and triggering neuronal dysfunction (Wang Jianzhi, azurin Tau protein hyperphosphorylation mechanism and its role in neuronal degeneration in alzheimer disease [ J ]. Biochemical and biophysical progression 2012 ]. With the aggravation of global aging, the prevalence rate of AD rises year by year, bringing great life trouble to patients, and simultaneously bringing great economic pressure to the global medical system.
Currently, the treatment methods of AD mainly include two major categories, drug therapy and non-drug therapy. The drug therapy is mainly cholinesterase inhibitor, NMDA receptor antagonist and anti-beta-amyloid drug, cholinesterase inhibitor (such as donepezil, galantamine, rismin and the like) is one of the main drugs clinically approved for AD therapy at present, and the non-drug intervention methods such as cognitive training, psychological therapy and music, aromatherapy （Victoria García-Morales, Anabel Gónzalez-Acedo et al. "Current Understanding of the Physiopathology, Diagnosis and Therapeutic Approach to Alzheimer's Disease." Biomedicines(2021).）. have been demonstrated to improve sleep, emotion and behavior of AD patients by increasing the concentration of acetylcholine in the brain to improve the cognitive function （R. Malik, Sunishtha Kalra et al. "Overview of therapeutic targets in management of dementia.." Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie(2022).）;NMDA receptor antagonist (Memantine) of patients, a low affinity NMDA receptor antagonist, protecting neurons by reducing excitotoxicity, drugs suitable for moderately severe AD patients （M. Prince, D. Acosta et al. "Packages of Care for Dementia in Low- and Middle-Income Countries." PLoS Medicine(2009).. Martin J. Prince, Daisy Acosta.）; against A beta pathology including monoclonal antibodies (such as A Du Kashan antibody, sorazamab and the like), and these drugs delay the progression of disease （Z. Fišar. "Linking the Amyloid, Tau, and Mitochondrial Hypotheses of Alzheimer's Disease and Identifying Promising Drug Targets." Biomolecules(2022).）. by clearing the A beta plaques in the brain including lifestyle intervention such as exercise training, diet conditioning and sleep management （M. Prince, D. Acosta et al. "Packages of Care for Dementia in Low- and Middle-Income Countries." PLoS Medicine(2009).）.
Recent studies have shown that some natural and synthetic compounds can act on the pathological processes of AD through multiple biological pathways, exerting anti-inflammatory, antioxidant, and aβ scavenging effects. For example, natural compounds such as curcumin, resveratrol, etc. can reduce neuroinflammation and improve nerve function by activating AMPK pathway or inhibiting NF- κB signaling pathway, rhodiola rosea and ginsenoside Rg1 can inhibit Abeta aggregation by crossing blood brain barrier through the actions of antioxidation, anti-inflammation and promoting nerve regeneration, while some synthetic compounds (such as BACE1 inhibitor and metal ion chelating agent) can show potential in preventing Abeta generation. In addition, studies of the gut-brain axis also revealed that intestinal microbial metabolites (e.g., short chain fatty acids) may further delay the progression of AD by modulating neuroimmune responses and brain metabolism.
However, the pathological mechanism of AD is complex, and there are significant differences between different patients, resulting in different therapeutic effects, and the existing therapeutic schemes generally have the defects of limited curative effect, single target point, obvious side effects, and the like, and it is difficult to fundamentally improve the symptoms of AD and delay the course of disease （A. E. Abdallah. "Review on anti-alzheimer drug development: approaches, challenges and perspectives." RSC Advances(2024).）., so that there is an urgent need to develop innovative therapeutic methods with multi-target effect, higher curative effect and better safety.
In the previous study （"Evolution of an antifreeze protein by neofunctionalization under escape from adaptive conflict",Deng et al.PNAS, 2010.）, was first found and demonstrated that Antarctic fish Lycodichthys dearborni evolved an antifreeze protein AFPIII by new functionalization during the course of getting rid of the adaptation conflicts, and named LdAFPII, which was evolved from SAS-B, and there was a duplication of multiple functional domains (such as LdAFPIII-1 for one duplicated functional domain, ldAFPIII-4 for four duplicated functional domains, ldAFPIII-12 for twelve duplicated functional domains, etc.), each AFPIII domain contained 62 amino acids. The sequence of LdAFPII proteins is disclosed by prior studies ("cloning and evolution analysis of the Antarctic Eul Pout (Lycodichthys dearborni) multimeric type III antifreeze protein gene", et al, genetics report, 2005,32 (8): 789-794.). Each AFPIII structural domain contains 62 amino acids, and the protein structure is predicted and optimized by alphafold3, so that the amino acids at 36 th and 37 th positions are changed from KL to RI, and the amino acid at 50 th position is changed from D to E, thereby increasing the flexibility of the protein structure. To explore its use in neurological diseases, it was named NeuroProtection AFPIII (e.g., NPAFP1, NPAFP, NPAFP, etc.). The NPAFP proteins of different domains have different antifreeze capacity, wherein NPAFP contains one AFPIII domain, NPAFP4 contains four AFPIII domains, and NPAFP12 contains twelve AFPIII domains.
There is no study of NPAFP protein in treating Alzheimer's disease.
Disclosure of Invention
In the application, NPAFP protein can improve the pathological characteristics of Alzheimer's disease through multiple mechanisms such as antioxidation, improvement of mitochondrial quality, reduction of Abeta 42 secretion, tau PFF and the like, and has the effect of preventing/treating Alzheimer's disease. Based on this, the present application has been completed.
In a first aspect, the invention provides a pharmaceutical composition for preventing and/or treating alzheimer's disease, said pharmaceutical composition comprising NPAFP proteins, said NPAFP proteins being selected from one or more of NPAFP1, NPAFP2, NPAFP3, NPAFP4, NPAFP5, NPAFP6, NPAFP7, NPAFP8, NPAFP, NPAFP10, NPAFP11 and/or NPAFP 12.
Further, the NPAFP protein is preferably one or more of NPAFP1, NPAFP2, NPAFP, NPAFP and/or NPAFP12, the nucleotide sequences of the NPAFP1, NPAFP2, NPAFP3, NPAFP and NPAFP proteins are respectively shown as SEQ ID NO 1-5, and the amino acid sequences of the NPAFP proteins are respectively shown as SEQ ID NO 6-10.
Further, the NPAFP protein can improve the anti-oxidative stress capability.
Still further, the NPAFP protein can increase cell viability.
Still further, the NPAFP protein is capable of reducing ROS levels.
Further, the NPAFP protein is capable of reducing aβ42 secretion in a subject.
Further, the NPAFP protein can reduce the pathological condition of Alzheimer's disease caused by Tau PFF.
Further, the pharmaceutical composition may further contain other active ingredients for preventing/treating Alzheimer's disease.
Further, one or more pharmaceutically acceptable carriers may be added to the pharmaceutical composition.
Furthermore, the pharmaceutical composition can be prepared into various forms such as tablets, powder, granules, capsules, oral liquid, injection preparations or aerosols, and the like, and the medicaments of the various forms can be prepared according to the conventional method in the pharmaceutical field.
Further, the formulation may be one or more of a general formulation, a slow release formulation, a controlled release formulation, and/or various microparticle delivery systems.
Further, the tablet may be widely used with various carriers known in the art, including one or more of diluents and absorbents, wetting agents and binders, disintegrants, disintegration inhibitors, absorption promoters, and/or lubricants.
Still further, the diluents and absorbents include, but are not limited to, one or more of starch, dextrin, calcium sulfate, lactose, mannitol, sucrose, sodium chloride, glucose, urea, calcium carbonate, kaolin, microcrystalline cellulose, and/or aluminum silicate.
Further, the humectants and binders include, but are not limited to, one or more of water, glycerin, polyethylene glycol, ethanol, propanol, starch slurry, dextrin, syrup, honey, dextrose solution, acacia slurry, gelatin slurry, sodium carboxymethyl cellulose, shellac, methyl cellulose, potassium phosphate and/or polyvinylpyrrolidone.
Further, the disintegrants include, but are not limited to, one or more of dry starch, alginate, agar powder, brown algae starch, sodium bicarbonate and citric acid, calcium carbonate, polyoxyethylene, sorbitol fatty acid ester, sodium dodecyl sulfonate, methylcellulose and/or ethylcellulose.
Further, the disintegration inhibitors include, but are not limited to, sucrose, glyceryl tristearate, cocoa butter and/or hydrogenated oils and the like.
Further, the absorption enhancer includes, but is not limited to, one or more of a quaternary ammonium salt and/or sodium dodecyl sulfate.
Further, the lubricant includes, but is not limited to, one or more of talc, silica, corn starch, stearate, boric acid, liquid paraffin, and/or polyethylene glycol.
Further, the tablets may be further formulated into coated tablets including sugar coated tablets, film coated tablets, enteric coated tablets, bilayer tablets and multilayer tablets.
Further, the injectable formulation includes, but is not limited to, one or more of a solution, an emulsion, a lyophilized powder for injection, and/or a suspension.
Still further, the injectable formulation may use all diluents commonly used in the art including, but not limited to, one or more of water, ethanol, polyethylene glycol, 1, 3-propanediol, ethoxylated isostearyl alcohol, polyoxidated isostearyl alcohol and/or polyoxyethylene sorbitol fatty acid esters.
Further, in order to prepare the isotonic injection, an appropriate amount of one or more of sodium chloride, glucose, glycerin, a conventional cosolvent, a buffer, and/or a pH adjuster may be added to the injection preparation.
Further, the various formulations may also incorporate colorants, preservatives, flavors, flavoring agents, sweeteners, or other materials into the pharmaceutical formulation as desired.
Further, the pharmaceutical composition may be introduced into the body by physical or chemical mediated methods such as muscle, intradermal, subcutaneous or intravenous.
In a second aspect, the invention provides application of NPAFP protein in preparing a medicament for preventing and/or treating Alzheimer's disease, wherein the NPAFP protein is selected from one or more of NPAFP1, NPAFP2, NPAFP3, NPAFP4, NPAFP5, NPAFP6, NPAFP7, NPAFP8, NPAFP9, NPAFP10, NPAFP11 and/or NPAFP 12.
Further, the NPAFP protein is preferably one or more of NPAFP1, NPAFP2, NPAFP, NPAFP and/or NPAFP protein, the nucleotide sequences of the NPAFP1, NPAFP, NPAFP3, NPAFP and NPAFP proteins are respectively shown as SEQ ID NO. 1-5, and the amino acid sequences of the NPAFP proteins are respectively shown as SEQ ID NO. 6-10.
Further, the NPAFP protein increases the antioxidant stress capacity.
Still further, the NPAFP protein increases cell viability and/or decreases ROS levels.
Further, the NPAFP protein reduces aβ42 secretion in the subject.
Further, the NPAFP protein reduces the pathological condition of Alzheimer's disease caused by Tau PFF.
Further, the pharmaceutical composition may further contain other active ingredients for preventing/treating Alzheimer's disease.
Further, one or more pharmaceutically acceptable carriers may be added to the pharmaceutical composition.
Furthermore, the pharmaceutical composition can be prepared into various forms such as tablets, powder, granules, capsules, oral liquid, injection preparations or aerosols, and the like, and the medicaments of the various forms can be prepared according to the conventional method in the pharmaceutical field.
Further, the formulation may be one or more of a general formulation, a slow release formulation, a controlled release formulation, and/or various microparticle delivery systems.
Further, the tablet may be widely used with various carriers known in the art, including one or more of diluents and absorbents, wetting agents and binders, disintegrants, disintegration inhibitors, absorption promoters, and/or lubricants.
Still further, the diluents and absorbents include, but are not limited to, one or more of starch, dextrin, calcium sulfate, lactose, mannitol, sucrose, sodium chloride, glucose, urea, calcium carbonate, kaolin, microcrystalline cellulose, and/or aluminum silicate.
Further, the humectants and binders include, but are not limited to, one or more of water, glycerin, polyethylene glycol, ethanol, propanol, starch slurry, dextrin, syrup, honey, dextrose solution, acacia slurry, gelatin slurry, sodium carboxymethyl cellulose, shellac, methyl cellulose, potassium phosphate and/or polyvinylpyrrolidone.
Further, the disintegrants include, but are not limited to, one or more of dry starch, alginate, agar powder, brown algae starch, sodium bicarbonate and citric acid, calcium carbonate, polyoxyethylene, sorbitol fatty acid ester, sodium dodecyl sulfonate, methylcellulose and/or ethylcellulose.
Further, the disintegration inhibitors include, but are not limited to, sucrose, glyceryl tristearate, cocoa butter and/or hydrogenated oils and the like.
Further, the absorption enhancer includes, but is not limited to, one or more of a quaternary ammonium salt and/or sodium dodecyl sulfate.
Further, the lubricant includes, but is not limited to, one or more of talc, silica, corn starch, stearate, boric acid, liquid paraffin, and/or polyethylene glycol.
Further, the tablets may be further formulated into coated tablets including sugar coated tablets, film coated tablets, enteric coated tablets, bilayer tablets and multilayer tablets.
Further, the injectable formulation includes, but is not limited to, one or more of a solution, an emulsion, a lyophilized powder for injection, and/or a suspension.
Still further, the injectable formulation may use all diluents commonly used in the art including, but not limited to, one or more of water, ethanol, polyethylene glycol, 1, 3-propanediol, ethoxylated isostearyl alcohol, polyoxidated isostearyl alcohol and/or polyoxyethylene sorbitol fatty acid esters.
Further, in order to prepare the isotonic injection, an appropriate amount of one or more of sodium chloride, glucose, glycerin, a conventional cosolvent, a buffer, and/or a pH adjuster may be added to the injection preparation.
Further, the various formulations may also incorporate colorants, preservatives, flavors, flavoring agents, sweeteners, or other materials into the pharmaceutical formulation as desired.
Further, the pharmaceutical composition may be introduced into the body by physical or chemical mediated methods such as muscle, intradermal, subcutaneous or intravenous.
In a third aspect, the invention provides a product for preventing and/or treating Alzheimer's disease, the product comprising NPAFP protein, the NPAFP protein being selected from one or more of NPAFP1, NPAFP2, NPAFP3, NPAFP4, NPAFP5, NPAFP, NPAFP7, NPAFP8, NPAFP9, NPAFP10, NPAFP11 and/or NPAFP 12.
Further, the NPAFP protein is preferably one or more of NPAFP1, NPAFP2, NPAFP, NPAFP and/or NPAFP12, the nucleotide sequences of the NPAFP1, NPAFP2, NPAFP3, NPAFP and NPAFP proteins are respectively shown as SEQ ID NO 1-5, and the amino acid sequences of the NPAFP proteins are respectively shown as SEQ ID NO 6-10.
Further, the NPAFP protein can improve the anti-oxidative stress capability.
Still further, the NPAFP protein can increase cell viability.
Still further, the NPAFP protein is capable of reducing ROS levels.
Further, the NPAFP protein is capable of reducing aβ42 secretion in a subject.
Further, the NPAFP protein can reduce the pathological condition of Alzheimer's disease caused by Tau PFF.
Further, the products include, but are not limited to, health products, functional foods, or laboratory reagents.
In a fourth aspect, the invention provides the use of a NPAFP protein for the preparation of a product for the prevention and/or treatment of alzheimer's disease, said NPAFP protein being selected from one or more of NPAFP1, NPAFP2, NPAFP3, NPAFP4, NPAFP5, NPAFP6, NPAFP7, NPAFP8, NPAFP9, NPAFP10, NPAFP11 and/or NPAFP 12.
Further, the NPAFP protein is preferably one or more of NPAFP1, NPAFP2, NPAFP, NPAFP and/or NPAFP12, the nucleotide sequences of the NPAFP1, NPAFP2, NPAFP3, NPAFP and NPAFP proteins are respectively shown as SEQ ID NO 1-5, and the amino acid sequences of the NPAFP proteins are respectively shown as SEQ ID NO 6-10.
Further, the NPAFP protein can improve the anti-oxidative stress capability.
Still further, the NPAFP protein can increase cell viability.
Still further, the NPAFP protein is capable of reducing ROS levels.
Further, the NPAFP protein is capable of reducing aβ42 secretion in a subject.
Further, the NPAFP protein can reduce the pathological condition of Alzheimer's disease caused by Tau PFF.
Further, the products include, but are not limited to, health products, functional foods, or laboratory reagents.
In a fifth aspect, the invention provides the use of a NPAFP protein selected from one or more of NPAFP1, NPAFP2, NPAFP3, NPAFP4, NPAFP5, NPAFP6, NPAFP7, NPAFP8, NPAFP9, NPAFP, NPAFP11 and/or NPAFP in the construction of a biological model against alzheimer's disease.
Further, the NPAFP protein is preferably one or more of NPAFP1, NPAFP2, NPAFP, NPAFP and/or NPAFP12, the nucleotide sequences of the NPAFP1, NPAFP2, NPAFP3, NPAFP and NPAFP proteins are respectively shown as SEQ ID NO 1-5, and the amino acid sequences of the NPAFP proteins are respectively shown as SEQ ID NO 6-10.
Further, the biological model includes, but is not limited to, a mammalian model and an aquatic biological model.
Further, the NPAFP protein can improve the anti-oxidative stress capability.
Still further, the NPAFP protein can increase cell viability.
Still further, the NPAFP protein is capable of reducing ROS levels.
Further, the NPAFP protein is capable of reducing aβ42 secretion in a subject.
Further, the NPAFP protein can reduce the pathological condition of Alzheimer's disease caused by Tau PFF.
Advantageous effects
The invention provides a pharmaceutical composition based on NPAFP protein, which can play a role in a plurality of pathological layers by utilizing the synergistic effect of natural and artificial compounds and remarkably improve AD symptoms. The composition has remarkable effects of resisting oxidation, resisting inflammation, promoting Abeta clearance, improving mitochondrial quality, reducing Abeta 42 secretion and pathological conditions caused by Tau PFF, and the like, and can protect neurons by regulating metabolic processes. The compound with synergistic effect is screened and optimized, so that the action mechanism of the compound is further defined, a novel safe and efficient potential solution is provided for the treatment of AD, and the compound has wide clinical application prospect. The medicine has high safety, strong specificity, simple preparation method and mass production.
Drawings
FIG. 1 shows NPAFP proteins to increase the antioxidant stress capacity of 293T cells.
Note that (A) the plasmid structure of NPAFP gene, (B) CCK8 measures the survival rate of cells, and (C) relative ROS content measurement.
FIG. 2 shows that NPAFP protein enhances mitochondrial quality in APP cells.
Note that (A) mitochondrial TOM20 staining of wild SY5Y cells, (B) mitochondrial TOM20 staining of the transgenic NPAFP gene and empty plasmid, and (C) relative fluorescence intensity statistics after TOM20 staining.
FIG. 3 shows NPAFP protein reduction of Abeta secretion by APP cells.
FIG. 4 shows the pathological state of Alzheimer's disease caused by NPAFP protein lowering Tau PFF.
Detailed Description
The following describes the invention in more detail. The description of these embodiments is provided to assist understanding of the present invention, but is not intended to limit the present invention. In addition, the technical features of the embodiments described below may be combined with each other as long as they do not collide with each other.
The experimental methods in the following examples, unless otherwise specified, are conventional, and the experimental materials used in the following examples, unless otherwise specified, are commercially available.
Interpretation of the terms
SY5Y cells are human neuroblastoma cell lines derived from human brain malignant neuroblastoma, have high proliferation capacity and differentiation potential, express various receptors and proteins on the cell surface, such as TrkA, BDNF receptors and the like, play an important role in neuronal functions and signal transduction, express neuronal markers (such as neurofilament proteins, synaptocins and the like) in the cell differentiation process, show certain neuroblastoma-like characteristics and are widely used in neuroscience research.
293T cells were derived from the 293 cell line (HEK 293), which was established by introducing the SV 40T antigen gene into human embryonic kidney cells. 293T cells retain many of the characteristics of 293 cell lines, including the high efficiency of protein expression and the genetic background for ease of manipulation. Is a mammalian cell line widely used in biomedical research, which is derived from human embryonic kidney cells and is transformed by adenovirus vectors. Such cell lines are widely used because of their high transfection efficiency, ease of culture and flexibility in genetic manipulation.
NPAFP DNA sequence
NPAFP1 DNA sequence:
ATGAAGTCAGTTGTTTTAACTGGTTTGCTGTTCGTCCTCCTTTGTGTCGACCACATGAGTTCAGCCAACAAGGCGTCCGTGGTGGCCAACCAGCTGATCCCCATAAATACTGCCCTGACTCTAGTGATGATGAAGGCGGAGGAAGTCAGCCCAAAGGGCATCCCTGCCGAGGAGATCCCCAGAATAGTGGGAATGCAAGTGAACAGGGCAGTGTATCTGGAGCAAACCCTCATGCCAGATATGGTGAAAAACTATGAATAA
NPAFP2 DNA sequence:
ATGAAGTCAGTTGTTTTAACTGGTTTGCTGTTCGTCCTCCTTTGTGTCGACCACATGAGTTCAGCCAACAAGGCGTCCGTGGTGGCCAACCAGCTGATCCCCATAAATACTGCCCTGACTCTAGTGATGATGAAGGCGGAGGAAGTCAGCCCAAAGGGCATCCCTGCCGAGGAGATCCCCAGAATAGTGGGAATGCAAGTGAACAGGGCAGTGTATCTGGAGCAAACCCTCATGCCAGATATGGTGAAAAACTATGAAGATGTGACGACATGTCCAGGCTTTAAGTCCGTGGTGGCCAACCAGCTGATCCCCATAAATACTGCCCTGACTCTAGTGATGATGAAGGCGGAGGAAGTCAGCCCAAAGGGCATCCCTGCCGAGGAGATCCCCAGAATAGTGGGAATGCAAGTGAACAGGGCAGTGTATCTGGAGCAAACCCTCATGCCAGATATGGTGAAAAACTATGAATAA
NPAFP3 DNA sequence:
ATGAAGTCAGTTGTTTTAACTGGTTTGCTGTTCGTCCTCCTTTGTGTCGACCACATGAGTTCAGCCAACAAGGCGTCCGTGGTGGCCAACCAGCTGATCCCCATAAATACTGCCCTGACTCTAGTGATGATGAAGGCGGAGGAAGTCAGCCCAAAGGGCATCCCTGCCGAGGAGATCCCCAGAATAGTGGGAATGCAAGTGAACAGGGCAGTGTATCTGGAGCAAACCCTCATGCCAGATATGGTGAAAAACTATGAAGATGTGACGACATGTCCAGGCTTTAAGTCCGTGGTGGCCAACCAGCTGATCCCCATAAATACTGCCCTGACTCTAGTGATGATGAAGGCGGAGGAAGTCAGCCCAAAGGGCATCCCTGCCGAGGAGATCCCCAGAATAGTGGGAATGCAAGTGAACAGGGCAGTGTATCTGGAGCAAACCCTCATGCCAGATATGGTGAAAAACTATGAAGATGTGACGACATGTCCAGGCTTTAAGTCCGTGGTGGCCAACCAGCTGATCCCCATAAATACTGCCCTGACTCTAGTGATGATGAAGGCGGAGGAAGTCAGCCCAAAGGGCATCCCTGCCGAGGAGATCCCCAGAATAGTGGGAATGCAAGTGAACAGGGCAGTGTATCTGGAGCAAACCCTCATGCCAGATATGGTGAAAAACTATGAA
NPAFP4 DNA sequence:
ATGAAGTCAGTTGTTTTAACTGGTTTGCTGTTCGTCCTCCTTTGTGTCGACCACATGAGTTCAGCCAACAAGGCGTCCGTGGTGGCCAACCAGCTGATCCCCATAAATACTGCCCTGACTCTAGTGATGATGAAGGCGGAGGAAGTCAGCCCAAAGGGCATCCCTGCCGAGGAGATCCCCAGAATAGTGGGAATGCAAGTGAACAGGGCAGTGTATCTGGAGCAAACCCTCATGCCAGATATGGTGAAAAACTATGAAGATGTGACGACATGTCCAGGCTTTAAGTCCGTGGTGGCCAACCAGCTGATCCCCATAAATACTGCCCTGACTCTAGTGATGATGAAGGCGGAGGAAGTCAGCCCAAAGGGCATCCCTGCCGAGGAGATCCCCAGAATAGTGGGAATGCAAGTGAACAGGGCAGTGTATCTGGAGCAAACCCTCATGCCAGATATGGTGAAAAACTATGAAGATGTGACGACATGTCCAGGCTTTAAGTCCGTGGTGGCCAACCAGCTGATCCCCATAAATACTGCCCTGACTCTAGTGATGATGAAGGCGGAGGAAGTCAGCCCAAAGGGCATCCCTGCCGAGGAGATCCCCAGAATAGTGGGAATGCAAGTGAACAGGGCAGTGTATCTGGAGCAAACCCTCATGCCAGATATGGTGAAAAACTATGAAGATGTGACGACATGTCCAGGCTTTAAGTCCGTGGTGGCCAACCAGCTGATCCCCATAAATACTGCCCTGACTCTAGTGATGATGAAGGCGGAGGAAGTCAGCCCAAAGGGCATCCCTGCCGAGGAGATCCCCAGAATAGTGGGAATGCAAGTGAACAGGGCAGTGTATCTGGAGCAAACCCTCATGCCAGATATGGTGAAAAACTATGAATAA
NPAFP12 DNA sequence:
ATGAAGTCAGTTGTTTTAACTGGTTTGCTGTTCGTCCTCCTTTGTGTCGACCACATGAGTTCAGCCAACAAGGCGTCCGTGGTGGCCAACCAGCTGATCCCCATAAATACTGCCCTGACTCTAGTGATGATGAAGGCGGAGGAAGTCAGCCCAAAGGGCATCCCTGCCGAGGAGATCCCCAGAATAGTGGGAATGCAAGTGAACAGGGCAGTGTATCTGGAGCAAACCCTCATGCCAGATATGGTGAAAAACTATGAAGATGTGACGACATGTCCAGGCTTTAAGTCCGTGGTGGCCAACCAGCTGATCCCCATAAATACTGCCCTGACTCTAGTGATGATGAAGGCGGAGGAAGTCAGCCCAAAGGGCATCCCTGCCGAGGAGATCCCCAGAATAGTGGGAATGCAAGTGAACAGGGCAGTGTATCTGGAGCAAACCCTCATGCCAGATATGGTGAAAAACTATGAAGATGTGACGACATGTCCAGGCTTTAAGTCCGTGGTGGCCAACCAGCTGATCCCCATAAATACTGCCCTGACTCTAGTGATGATGAAGGCGGAGGAAGTCAGCCCAAAGGGCATCCCTGCCGAGGAGATCCCCAGAATAGTGGGAATGCAAGTGAACAGGGCAGTGTATCTGGAGCAAACCCTCATGCCAGATATGGTGAAAAACTATGAAGATGTGACGACATGTCCAGGCTTTAAGTCCGTGGTGGCCAACCAGCTGATCCCCATAAATACTGCCCTGACTCTAGTGATGATGAAGGCGGAGGAAGTCAGCCCAAAGGGCATCCCTGCCGAGGAGATCCCCAGAATAGTGGGAATGCAAGTGAACAGGGCAGTGTATCTGGAGCAAACCCTCATGCCAGATATGGTGAAAAACTATGAAGATGTGACGACATGTCCAGGCTTTAAGTCCGTGGTGGCCAACCAGCTGATCCCCATAAATACTGCCCTGACTCTAGTGATGATGAAGGCGGAGGAAGTCAGCCCAAAGGGCATCCCTGCCGAGGAGATCCCCAGAATAGTGGGAATGCAAGTGAACAGGGCAGTGTATCTGGAGCAAACCCTCATGCCAGATATGGTGAAAAACTATGAAGATGTGACGACATGTCCAGGCTTTAAGTCCGTGGTGGCCAACCAGCTGATCCCCATAAATACTGCCCTGACTCTAGTGATGATGAAGGCGGAGGAAGTCAGCCCAAAGGGCATCCCTGCCGAGGAGATCCCCAGAATAGTGGGAATGCAAGTGAACAGGGCAGTGTATCTGGAGCAAACCCTCATGCCAGATATGGTGAAAAACTATGAAGATGTGACGACATGTCCAGGCTTTAAGTCCGTGGTGGCCAACCAGCTGATCCCCATAAATACTGCCCTGACTCTAGTGATGATGAAGGCGGAGGAAGTCAGCCCAAAGGGCATCCCTGCCGAGGAGATCCCCAGAATAGTGGGAATGCAAGTGAACAGGGCAGTGTATCTGGAGCAAACCCTCATGCCAGATATGGTGAAAAACTATGAAGATGTGACGACATGTCCAGGCTTTAAGTCCGTGGTGGCCAACCAGCTGATCCCCATAAATACTGCCCTGACTCTAGTGATGATGAAGGCGGAGGAAGTCAGCCCAAAGGGCATCCCTGCCGAGGAGATCCCCAGAATAGTGGGAATGCAAGTGAACAGGGCAGTGTATCTGGAGCAAACCCTCATGCCAGATATGGTGAAAAACTATGAAGATGTGACGACATGTCCAGGCTTTAAGTCCGTGGTGGCCAACCAGCTGATCCCCATAAATACTGCCCTGACTCTAGTGATGATGAAGGCGGAGGAAGTCAGCCCAAAGGGCATCCCTGCCGAGGAGATCCCCAGAATAGTGGGAATGCAAGTGAACAGGGCAGTGTATCTGGAGCAAACCCTCATGCCAGATATGGTGAAAAACTATGAAGATGTGACGACATGTCCAGGCTTTAAGTCCGTGGTGGCCAACCAGCTGATCCCCATAAATACTGCCCTGACTCTAGTGATGATGAAGGCGGAGGAAGTCAGCCCAAAGGGCATCCCTGCCGAGGAGATCCCCAGAATAGTGGGAATGCAAGTGAACAGGGCAGTGTATCTGGAGCAAACCCTCATGCCAGATATGGTGAAAAACTATGAAGATGTGACGACATGTCCAGGCTTTAAGTCCGTGGTGGCCAACCAGCTGATCCCCATAAATACTGCCCTGACTCTAGTGATGATGAAGGCGGAGGAAGTCAGCCCAAAGGGCATCCCTGCCGAGGAGATCCCCAGAATAGTGGGAATGCAAGTGAACAGGGCAGTGTATCTGGAGCAAACCCTCATGCCAGATATGGTGAAAAACTATGAAGATGTGACGACATGTCCAGGCTTTAAGTCCGTGGTGGCCAACCAGCTGATCCCCATAAATACTGCCCTGACTCTAGTGATGATGAAGGCGGAGGAAGTCAGCCCAAAGGGCATCCCTGCCGAGGAGATCCCCAGAATAGTGGGAATGCAAGTGAACAGGGCAGTGTATCTGGAGCAAACCCTCATGCCAGATATGGTGAAAAACTATGAATAA
NPAFP amino acid sequence
NPAFP1 amino acid sequence of 1:
MKSVVLTGLLFVLLCVDHMSSANKASVVANQLIPINTALTLVMMKAEEVSPKGIPAEEIPRIVGMQANRAVYLEQTLMPDMVKNYE
NPAFP2 amino acid sequence of seq id no:
MKSVVLTGLLFVLLCVDHMSSANKASVVANQLIPINTALTLVMMKAEEVSPKGIPAEEIPRIVGMQANRAVYLEQTLMPDMVKNYEDGTTCPGIKSVVANQLIPINTALTLVMMKAEEVSPKGIPAEEIPRIVGMQANRAVYLEQTLMPDMVKNYE
NPAFP3 amino acid sequence:
MKSVVLTGLLFVLLCVDHMSSANKASVVANQLIPINTALTLVMMKAEEVSPKGIPAEEIPRIVGMQANRAVYLEQTLMPDMVKNYEDGTTCPGIKSVVANQLIPINTALTLVMMKAEEVSPKGIPAEEIPRIVGMQANRAVYLEQTLMPDMVKNYEDGTTCPGIKSVVANQLIPINTALTLVMMKAEEVSPKGIPAEEIPRIVGMQANRAVYLEQTLMPDMVKNYE
NPAFP4 amino acid sequence of 4:
MKSVVLTGLLFVLLCVDHMSSANKASVVANQLIPINTALTLVMMKAEEVSPKGIPAEEIPRIVGMQANRAVYLEQTLMPDMVKNYEDGTTCPGIKSVVANQLIPINTALTLVMMKAEEVSPKGIPAEEIPRIVGMQANRAVYLEQTLMPDMVKNYEDGTTCPGIKSVVANQLIPINTALTLVMMKAEEVSPKGIPAEEIPRIVGMQANRAVYLEQTLMPDMVKNYEDGTTCPGIKSVVANQLIPINTALTLVMMKAEEVSPKGIPAEEIPRIVGMQANRAVYLEQTLMPDMVKNYE
NPAFP12 amino acid sequence of seq id no:
MKSVVLTGLLFVLLCVDHMSSANKASVVANQLIPINTALTLVMMKAEEVSPKGIPAEEIPRIVGMQANRAVYLEQTLMPDMVKNYEDGTTCPGIKSVVANQLIPINTALTLVMMKAEEVSPKGIPAEEIPRIVGMQANRAVYLEQTLMPDMVKNYEDGTTCPGIKSVVANQLIPINTALTLVMMKAEEVSPKGIPAEEIPRIVGMQANRAVYLEQTLMPDMVKNYEDGTTCPGIKSVVANQLIPINTALTLVMMKAEEVSPKGIPAEEIPRIVGMQANRAVYLEQTLMPDMVKNYEDGTTCPGIKSVVANQLIPINTALTLVMMKAEEVSPKGIPAEEIPRIVGMQANRAVYLEQTLMPDMVKNYEDGTTCPGIKSVVANQLIPINTALTLVMMKAEEVSPKGIPAEEIPRIVGMQANRAVYLEQTLMPDMVKNYEDGTTCPGIKSVVANQLIPINTALTLVMMKAEEVSPKGIPAEEIPRIVGMQANRAVYLEQTLMPDMVKNYEDGTTCPGIKSVVANQLIPINTALTLVMMKAEEVSPKGIPAEEIPRIVGMQANRAVYLEQTLMPDMVKNYEDGTTCPGIKSVVANQLIPINTALTLVMMKAEEVSPKGIPAEEIPRIVGMQANRAVYLEQTLMPDMVKNYEDGTTCPGIKSVVANQLIPINTALTLVMMKAEEVSPKGIPAEEIPRIVGMQANRAVYLEQTLMPDMVKNYEDGTTCPGIKSVVANQLIPINTALTLVMMKAEEVSPKGIPAEEIPRIVGMQANRAVYLEQTLMPDMVKNYEDGTTCPGIKSVVANQLIPINTALTLVMMKAEEVSPKGIPAEEIPRIVGMQANRAVYLEQTLMPDMVKNYE
example 1H 2O2 treatment to test the antioxidant Capacity of NPAFP protein
1.1 Test method
(1) Pretreatment of
Transferring the NPAFP expression plasmid into 293T cells by chemical transfection reagent, treating the cells with hydrogen peroxide (H 2O2), changing fresh culture medium, and culturing.
(2) CCK8 detection of cell viability
The method comprises the steps of replacing cells treated by H 2O2 with fresh culture medium, continuously culturing, adding CCK8 reagent, placing in an incubator for continuous incubation, reading OD value, carrying out ratio treatment on the OD value treated by H 2O2 and the untreated OD value, and counting survival rate.
(3) Intracellular ROS level detection
CM-H2DCFDA was diluted with serum-free medium to a final concentration of 5. Mu. Mol/liter. The method comprises the steps of collecting cells, suspending the cells in diluted CM-H2DCFDA for incubation, uniformly mixing and washing the cells to sufficiently remove the CM-H2DCFDA which does not enter the cells, detecting the cells by using a flow cytometry with 495 nm excitation light and 530 nm emission light, and counting the fluorescence intensity of ROS.
1.2 Test results
As shown in a in fig. 1, the antarctic fish NPAFP protein was obtained from a different number of tandem repeats of AFPIII domains, NPAFP contained one AFPIII domain, NPAFP contained two AFPIII domains, NPAFP3 contained three AFPIII domains, NPAFP4 contained four AFPIII domains, and NPAFP contained twelve AFPIII domains. NPAFP protein expression plasmids were transfected into 293T cells using chemical transfection reagents and treated with H 2O2 to examine cell viability and ROS levels. The results show that NPAFP protein expression can significantly increase cell viability (B in fig. 1) and decrease ROS levels in cells (C in fig. 1), indicating that NPAFP protein can increase the antioxidant stress capability of 293T cells, and that antioxidant capability is proportional to the number of AFPIII domains. This finding supports NPAFP's potential application value in antioxidation stress and prevention of AD.
EXAMPLE 2 immunofluorescence detection of mitochondrial mass
2.1 Test method
1) SH-SY5Y/WT and cells stably expressing Swedish mutant APP (SH-SY 5Y/APP695 swe) were selected as AD models;
2) Transfecting NPAFP gene expression plasmid into WT (SY 5Y) and APP (SH-SY 5Y/APP695 swe) cells, and performing immunofluorescent staining on the cells after transfection;
3) Triton X-100 treats the cell membrane so that antibodies can enter the cell;
4) Adding a primary antibody (anti-TOM 20), incubating, and removing unbound primary antibody after washing;
5) Adding secondary antibody (Alexa Fluor 594 labeled goat anti-rabbit IgG (H+L)), continuing incubation, washing, removing excessive secondary antibody, and sealing with anti-fluorescence attenuator;
6) Expression of TOM20 in cells was observed and recorded.
2.2 Test results
Wild-type cells (SH-SY 5Y/WT) and cells stably expressing Swedish familial mutant human APP695 (SHSY 5Y/APP695 swe) were used as a model of Alzheimer's disease cells with endogenous high expression of APP.
The NPAFP protein expression plasmid is transfected into the two cells (A in figure 2 and B in figure 2) by using a chemical transfection reagent, and immunofluorescent staining is carried out on the mitochondrial mass protein TOM20, so that the result shows that the NPAFP protein can significantly improve the mitochondrial mass of APP cells, and the effect is positively correlated with the AFPIII domain number in npafp gene (C in figure 2). This finding suggests the potential application value of NPAFP in the prevention of AD.
EXAMPLE 3 Abeta 42 secretion assay of APP cells
3.1 Test method
Detection of cell secreted aβ42 was by enzyme-linked immunosorbent assay (ELISA).
Transferring the constructed NPAFP expression plasmid into APP cells by using a chemical transfection reagent, and collecting cell supernatant. The supernatant was quantitatively analyzed for aβ42 using an ELISA kit. The capture antibody of the specific anti-Abeta 42 is coated on a microplate in advance, a sample is added after incubation, and Abeta 42 is combined with the capture antibody. Then, a labeled detection antibody is added, and after binding to aβ42, the antibody undergoes a color change by a substrate reaction, and the absorbance value is measured and compared with a standard curve to quantify the content of aβ42.
3.2 Test results
The Abeta protein is secreted and released into interstitial fluid under the condition of enhanced neuron activity, and is aggregated to form oligomers and fibrils, and finally plaque is formed, which is an important cause of Alzheimer's disease.
The NPAFP protein expression plasmid was transfected into APP695 cells (SHSY 5Y/APP695 swe) using a chemical transfection reagent, and the content of Abeta 42 in the cytoplasm was examined.
As shown in fig. 3, NPAFP protein was able to significantly reduce aβ42 secretion by APP695 cells, and the inhibitory effect was positively correlated with the number of AFPIII domains in the npafp gene. These results indicate that NPAFP protein has potential in reducing aβ accumulation, and can provide a new idea for AD treatment.
Example 4 pTau pathology detection of mice transformed with the Antarctic fish npafp Gene
4.1 Test method
12 Week old mice, 7WT mice, 10 test mice were selected for transgenic treatment.
Tau PFF expressed in vitro was injected into WT (C57 BL 6) and hippocampus of npafp, npafp4 and npafp gene-heterozygous mice by stereotactic injection. Hippocampal region vaccinated tau PFF, WT and transgenic mice (n=7 and 10) were pathologically examined at 3 months (3 mpi).
To confirm pathological transformation, hyperphosphorylated Tau (pTau) deposition was detected after a single inoculation of PFF 3 mpi.
The whole brain was fixed after the mice were perfused, and then dehydrated with sucrose solution. Immunohistochemical (IHC) assays were performed on brain frozen sections. Primary antibody and working dilutions p-Tau 1:500, sections labeled with primary antibody were incubated with horseradish peroxidase-labeled secondary antibody (Invitrogen). Observe the picture, take a photograph and record.
4.2 Test results
Abnormal aggregation of Tau protein is an important cause of alzheimer's disease.
As shown in a in fig. 4, tau PFF protein was injected into the hippocampal region of transgenic decimal by stereomicroinjection, and pathology of the hippocampal region was detected several months later.
As shown in B in fig. 4, NPAFP protein was found to significantly reduce the pathology of alzheimer's disease caused by Tau PFF, and the inhibitory effect was positively correlated with the number of AFPIII domains in npafp gene. These results indicate that NPAFP protein has potential in reducing the pathology caused by Tau PFF, and can provide a new idea for AD treatment. The NPAFP protein has multiple target actions, so that the NPAFP protein becomes a potential novel candidate drug for AD treatment, and has wide clinical application prospect.
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