CN101288768A - Pharmaceutical composition for treating progressive neurodegenerative disease - Google Patents

Abstract

The present invention provides a pharmaceutical composition for treating progressive neurodegeneration or inhibiting the onset of progressive neurodegeneration in a high-risk subject, comprising at least an effective amount of an agent acting as a granulocyte colony stimulating factor receptor, whereby hematopoietic stem cells migrate from the bone marrow to the peripheral blood. The composition can also be used to inhibit the development of progressive neurodegenerative disorders in high risk subjects. A method of selecting a highly potent granulocyte colony stimulating factor receptor agent for treating progressive neurodegenerative disorders is also provided.

Description

Pharmaceutical composition for the treatment of progressive neurodegeneration

technical field

The present invention relates to a pharmaceutical composition of a granulocyte colony-stimulating factor receptor agent and its use in the manufacture of medicines.

Background technique

Progressive neurodegenerative disorders (PNDs), such as Alzheimer's disease, cause slow but invariable neuronal loss accompanied by a reduction in cognitive or motor function, with the result being the death of the subject. Progressive neurodegeneration has a devastating impact on the quality of life of those affected and their families. In addition, progressive neurodegeneration imposes a heavy health care burden on society. In fact, such diseases mainly affect the expanding elderly population, so their prevalence and social impact are expected to increase in the coming years.

One of the most promising treatments for progressive neurodegeneration is neuron replacement with transplanted neurons derived from stem cells, which in very small numbers are dispersed in various tissues of the adult body, including the bone marrow. Human embryonic stem cells (HESCs) are considered the most potentially therapeutically useful. Unfortunately, the cultivation of human embryonic stem cell lines of sufficient quantity and quality for clinical application is severely restricted by the controversy over their fetal origin. However, even though clinical-grade hESC lines are readily available, transplanting neurons derived from in vitro differentiated HESCs is risky and requires highly invasive intracerebral injections to deliver neurons into the patient's brain. Therefore, there is an urgent and continuing need for low-risk and non-invasive neuronal replenishment methods for treating or inhibiting progressive neurodegeneration.

Description of drawings

The foregoing and the following detailed description of the invention will be better understood when taken with reference to the accompanying drawings. For the purpose of illustrating the invention, a presently preferred embodiment is shown in the drawings. It should be understood, however, that the invention is not limited to the methods shown.

In the attached picture:

Figure 1 is a long-term sustained effect of Tg2576 mice treated with granulocyte colony-stimulating factor (G-CSF). Cognitive performance was measured three months after Tg2576 mice were treated subcutaneously with PBS or granulocyte colony-stimulating factor using a water maze task test. And including the latency period of Tg2576 mice (control group) before treatment with PBS or granulocyte colony-stimulating factor for comparison.

Contents of the invention

The present invention is based, in part, on the finding that agents acting on granulocyte colony-stimulating factor receptor (G-CSFR) stimulate endogenous neurodegeneration when administered systemically to subjects suffering from progressive neurodegeneration (Endogenous) stem cells migrate from the bone marrow to degenerated brain regions such as the hippocampus and cortex to promote neurogenesis.

Therefore, one aspect of the present invention relates to a pharmaceutical composition for treating progressive neurodegeneration or inhibiting the occurrence of progressive neurodegeneration in high-risk subjects, which at least comprises an effective amount of a granulocyte colony-stimulating factor receptor agent, This allows hematopoietic stem cells to move from the bone marrow to the peripheral blood. Compositions of the invention are administered systemically to treat subjects suffering from progressive neurodegeneration. The systemically administered granulocyte colony-stimulating factor receptor agent can move hematopoietic stem cells from bone marrow to peripheral blood. Stem cells circulating in the peripheral blood can then cross the blood-brain barrier into degenerated brain regions. Systemic administration of a granulocyte colony-stimulating factor receptor agent or a pharmaceutical composition thereof for treating progressive neurodegeneration. The systemically administered granulocyte colony-stimulating factor receptor agent can move hematopoietic stem cells from bone marrow to peripheral blood. Stem cells circulating in the peripheral blood can then cross the blood-brain barrier into degenerated brain regions.

G-colony-stimulating factor receptor agent refers to a molecule that engages and activates the granulocyte-colony-stimulating factor receptor, eg, granulocyte-colony-stimulating factor itself, granulocyte-colony-stimulating factor sequence-related variant, granulocyte-colony-stimulating factor receptor Agent monoclonal antibody or antibody-derived polypeptide, or small molecular compound.

Progressive neurodegeneration includes any symptoms that result in the death of nerve cells over a period of more than three days, such as one month or twenty years, and the disorder manifests behaviorally as cognitive or motor deficits in the subject. normal and deteriorating. Before the administration of the medicament of the present invention, if the subject is diagnosed with progressive neurodegeneration, for example, in the behavioral function of the brain, progressive neurodegeneration includes those that reduce cognitive abilities (such as short-term memory, long-term memory, spatial orientation, Facial recognition or speech); in terms of brain structure, some progressive neurodegenerations are due to degeneration (at least in part) of the hippocampal or cortical neurons. Examples of progressive neurodegeneration are Alzheimer's, Parkinson's, Huntington's, Lewy Body Dementia or Pick's disease. It is worth noting that some progressive neurodegenerative disorders affect both cognition and motor function such as Huntington's disease.

Another aspect of the invention relates to inhibiting the onset of progressive neurodegeneration. In subjects at high risk (eg, diagnosed) of progressive neurodegeneration, systemic administration of a medicament comprising an effective amount of the invention can inhibit the development of progressive neurodegeneration.

Another aspect of the present invention relates to a selection method of a high-efficiency granulocyte colony-stimulating factor receptor agent (used to treat progressive neurodegeneration). The method involves systemically administering a granulocyte colony-stimulating factor receptor-acting agent to a non-human test mammal suffering from progressive neurodegeneration. The mammal's performance on a behavioral task is then measured and compared to a control group of mammals suffering from the same progressive neurodegeneration but not administered a granulocyte colony stimulating factor receptor-acting agent. Test mammals that perform better than control mammals indicate high efficacy of their granulocyte colony stimulating factor receptor acting agent for the treatment of progressive neurodegeneration. Test mammals and control mammals can be produced by biotechnological methods, including genetic modification and non-genetic methods, such as overexpression of a transgene to make them suffer from progressive neurodegeneration. In addition, aggregated beta-amyloid peptide (Aβ) can be administered to test mammals as well as control mammals to induce progressive neurodegeneration that impairs learning or memory.

Other features or advantages of the present invention will be better understood through the following detailed description and claims.

Detailed ways

Methods of treatment of subjects suffering from progressive neurodegeneration are described below. The methods comprise treating a subject suffering from progressive neurodegeneration by systemically administering a composition comprising an effective amount of a granulocyte colony stimulating factor receptor-acting agent. The granulocyte colony-stimulating factor receptor agent causes the migration of hematopoietic stem cells from the bone marrow to degenerated brain regions and promotes neurogenesis in the regions. The granulocyte colony stimulating factor receptor agent may also be administered to subjects at high risk of developing progressive neurodegeneration as a method of inhibiting its occurrence. The present invention also provides a method for selecting a potent granulocyte colony stimulating factor receptor agent (for the treatment of progressive neurodegeneration) by testing its efficacy in a non-human mammal suffering from progressive neurodegeneration.

The β-G-CSF receptor agent may be a purified mammalian polypeptide comprising the amino acid sequence of a mature mammalian β-G-CSF (eg, human or mouse β-G-CSF), in other words, it does not contain a signal peptide sequence. For example, a high-potency granulocyte colony-stimulating factor receptor agent may comprise amino acids 13-186 of human high-potency granulocyte colony-stimulating factor (GenBank Accession No. AAA03056):

TPLGPASSLPQSFLLKCLEQVRKIQGDGAALQEKLCATYKLCHPEELVLLGHSLGIPWAPLSSSCPSQALQLAGCLSQLHSGLFLYQGLLQALEGISPELGPTLDTLQLDVADFATTIWQQMEELGMAPALQPTQGAMPAFASAFQRRAGGVLVASHLQSFLEVSYRVLRHLAQP (SEQ ID NO: 1)

Mammalian high-efficiency granulocyte colony-stimulating factor or a polypeptide containing high-efficiency granulocyte colony-stimulating factor can be expressed from a natural source (native source) (such as a cell line that secretes native granulocyte colony-stimulating factor) or a recombinant expression source ( For example, purification of Escherichia coli, yeast, insect cells or mammalian cells expressing transgenic granulocyte colony-stimulating factor). Recombinant human G-CSF can also be purchased from a commercial source such as Amgen Biologicals (Thousand Oaks, CA). In addition, recombinant granulocyte colony-stimulating factor can also be purified in the manner described in US Pat. No. 5,849,883.

The granulocyte colony stimulating factor receptor agent may be a granulocyte colony stimulating factor sequence variant that is at least 70% (eg, any identical percentage between 70% and 100%) identical to SEQ ID NO: 1 (see U.S. Patent No. 6,358,505 and 6,632,426). In general, granulocyte colony stimulating factor sequence variants should not alter residues critical to granulocyte colony stimulating factor function, including (in human G-CSF) residues K16, E19, Q20, R22, K23 , D27, D109 and F144. See, eg, Young et al., id. and Example 29 of US Patent No. 6,358,505.

When comparing the granulocyte colony-stimulating factor sequence to the sequences of the sequence variants, the percent identity between the two sequences is a function of the number of identical positions between the sequences (and taking into account the number of gaps and the length of the gap, which is the difference between the two sequences The optimal alignment of is a must). A comparison of sequences and percent identity between two sequences can be achieved using a mathematical algorithm. The percent identity between two amino acid sequences can be determined using the algorithm incorporated into the GAP program of the GCG software package (Needleman and Wunsch (1970), J. Mol. Biol. 48: 444-453), using the Blossum 62 matrix or the PAM250 matrix and 16, Notch weighting of 14, 12, 10, 8, 6, or 4 and length weighting of 1, 2, 3, 4, 5, or 6.

The granulocyte colony stimulating factor receptor agent can be a chemically modified mammalian granulocyte colony stimulating factor such as that described in US Patent No. 5,824,778 having an ethylene glycol group linkage.

In addition, the granulocyte colony stimulating factor receptor agent can be a monoclonal antibody or an antibody-derived molecule (eg, a Fab fragment) capable of engaging and activating the granulocyte colony stimulating factor receptor, as described in US Patent Application No. 20030170237.

Preferably, the 50% effective concentration (EC50) of the granulocyte colony-stimulating factor receptor agent is no greater than ten times the 50% effective concentration of granulocyte colony-stimulating factor. In addition, the affinity of the granulocyte colony stimulating factor receptor agent is not less than one-tenth of the affinity of granulocyte colony stimulating factor. Determination of the properties of granulocyte colony-stimulating factor receptor-acting agents is detailed in Young et al. (1997), Protein Science 6: 1228-1236 and US Pat. No. 6,790,628. In addition, these assays can be used to identify entirely novel granulocyte colony-stimulating factor receptor agents (eg, small molecule agents) that meet the aforementioned criteria.

The granulocyte colony stimulating factor receptor agents described above are useful in the treatment of subjects suffering from progressive neurodegeneration that reduces cognitive performance. Examples of progressive neurodegenerative disorders affecting at least one cognitive ability include, but are not limited to, Alzheimer's disease, Huntington's disease, Lewy Body Dementia, or Pick's disease. The progressive neurodegeneration is treated by systemically administering to the subject a composition containing an effective amount of the aforementioned granulocyte colony-stimulating factor receptor-acting agent. A patient may be diagnosed as suffering from a progressive neurodegeneration prior to administration of the inhibitory composition. In the case of a disorder affecting cognition, the patient can be diagnosed using any of the standard cognitive assessments, such as the Mini-Mental State Examination, Blessed Information Memory Concentration assay, or Functional Activity Questionnaire. See Adelman et al. (2005), Am. Family Physician, 71(9): 1745-1750. Furthermore, in some instances, a subject may be diagnosed as being at high risk for progressive neurodegeneration even in the absence of overt symptoms. For example, the risk of Alzheimer's disease in a subject can be determined by measuring the volume of the hippocampus and amygdala of the subject using magnetic resonance imaging. See, eg, den Heijer et al. (2006), Arch. Gen. Psychiatry, 63(1):57-62. Thus, the risk of progressive neurodegeneration in a subject can be reduced by prophylactic administration of a composition comprising an effective amount of a granulocyte colony-stimulating factor receptor-acting agent.

Selection of highly potent granulocyte colony-stimulating factor receptor agents for the treatment of progressive neurodegeneration can be based on their evaluation in non-human mammals suffering from progressive neurodegeneration. The granulocyte colony-stimulating factor receptor agent to be tested is administered systemically to a test mammal suffering from a progressive neurodegeneration known to impair performance on a behavioral task. The test mammal's performance on the behavioral task is then assessed and compared to a control group of mammals suffering from the same progressive neurodegeneration but not administered the granulocyte colony stimulating factor receptor acting agent. The better performing test mammals showed high progressive neurodegeneration therapeutic efficacy of their granulocyte colony stimulating factor receptor acting agents.

A non-human mammal for testing on a behavioral task can be, for example, a rodent (eg, mouse, rat, or guinea pig). Non-rodent animals such as rabbits, cats or monkeys can also be used. In some instances, non-human mammals have been genetically engineered to exhibit progressive neurodegeneration. For example they may express a transgene or suppress the expression of a natural gene. The expression of the transgene or the suppression of the natural gene can be adjusted temporally or regionally. Methods of transgene expression or gene suppression and their spatial and temporal control in non-human mammals such as mice and other rodents have been established. See, e.g., Si-Hoe et al. (2001), Mol Biotechnol., 17(2): 151-182; Ristevski (2005), Mol. Biotechnol., 29(2): 153-163; and Deglon et al . (2005), J. Gene Med., 7(5): 530-539.

Gene transgenic mouse models of many progressive neurodegenerative diseases (such as Alzheimer's disease and amyotrophic lateral sclerosis (ALS)) have been established. See, eg, Spires et al. (2005), NeuroRx., 2(3):447-64 and Wong et al. (2002), Nat. Neurosci., 5(7):633-639. These transgenic animal models spontaneously exhibit progressive neurodegeneration manifested in impaired learning, memory or motor behaviour. These animal model lines are suitable for selection of highly potent granulocyte colony-stimulating factor receptor agents (as previously described).

Progressive neurodegeneration can also be induced non-genetically in non-human mammals. For example, an intracerebral injection of aggregated Aβ-type peptides (as described by Yan et al. (2001), Br. J. Pharmacol., 133(1): 89-96) can induce a phenotype that affects learning and memory. Progressive neurodegeneration in rodents.

Cognitive and motor function in non-human mammals with progressive neurodegeneration can be assessed using a number of behavioral tasks. Comprehensive and sensitive learning and memory assays including Morris watermaze, context-dependent fear conditioning, cued-fear conditioning and context-dependent discrimination ). See, eg, Anger (1991 ), Neurotoxicology, 12(3):403-413. Analysis of motor behavior/function included rotorod, treadmill running, and general motor assessment.

The aforementioned granulocyte colony-stimulating factor receptor acting agent can be added to pharmaceutical compositions for preventive or therapeutic purposes. For example, the pharmaceutical composition may comprise an effective amount of recombinant human granulocyte colony-stimulating factor receptor agent and a pharmaceutically acceptable carrier. "Effective amount" refers to the amount of the main ingredient required to impart a prophylactic or therapeutic effect to the subject being treated. In general, effective doses will result in circulating concentrations of granulocyte colony-stimulating factor receptor-acting agents sufficient to reliably increase the number of hematopoietic progenitor cells in circulating blood. Nevertheless, as recognized by those skilled in the art, effective doses will vary with the type of progressive neurodegenerative disorder being treated, its severity, the stage of intervention, the general health or age of the subject, previous therapy, route of administration, excipients and the possibility of concomitant use with other prophylaxis or treatment.

The method of practicing the present invention is systemic administration of a pharmaceutical composition containing a G-CSFR active agent via parenteral or rectal route. "Parenteral" as used herein means subcutaneous, intracutaneous, intravenous, intramuscular, intra-articular, intra-arterial Intra-arterial, intrasynovial, intrasternal, intrathecal, or intralesional, and any appropriate injection technique.

The pharmaceutical composition of the present invention is preferably administered in the form of a pyrogen-free parenteral acceptable aqueous solution. The preparation of parenteral acceptable protein aqueous solution with appropriate pH value, isotonicity and stability belongs to the skill of this technical field. Parenteral acceptable vehicles and solvents that can be used include mannitol, water, Ringer's solution and isotonic sodium chloride solution.

Because progressive neurodegeneration is a chronic condition, continuous systemic administration is useful for treating patients. Continuous infusion of a pharmaceutical composition and maintenance of its systemic concentration over a period of time is known in the art. For example, the pharmaceutical compositions described herein can be released or delivered by an osmotic minipump (or other Time Release device). The rate of release from the substantially osmotic micropump can be tuned using a microporous fast-response gel located in the release pores. Osmotic minipumps are suitable for controlled release of the composition over an extended period of time (one week to five weeks). These micropumps, like other sustained release devices, are commercially available from DURECT corporation (Cupertino, CA). The main ingredient can also be administered in the form of a suppository for rectal administration.

The following specific examples are presented by way of illustration and not in any way as limiting for the remainder of this specification. Without further elaboration, it is believed that one skilled in the art can, based on the description herein, utilize the present invention to its fullest extent. All publications cited herein are incorporated by reference in their entirety.

Example 1 Granulocyte colony-stimulating factor improves the learning disability (learningdeficit) of Alzheimer's disease mouse model

Alzheimer's-like progressive neurodegeneration was induced in mice by intraventricular injection of aggregated Aβ-type peptides (as previously described by Yan et al.)

Aggregated Aβ-type peptides were prepared from 10 mM soluble Aβ _(1-42) in 0.01 M phosphate buffer, pH 7.4. Aβ-type peptides were purchased from Sigma-Aldrich (St. Louis, MO). Aβ solutions were heated at 37°C for three days to form aggregated Aβ-type peptides and stored at -70°C before use. Eight-week-old C57BL/6 male mice were anesthetized with intraperitoneal sodium pentobarbital (40 mg/kg) before injection of aggregated Aβ-type peptides. The aggregated A[beta]-type peptides were then injected stereotaxically into the dorsal hippocampus and both sides of the cerebral cortex using a 26-gauge needle attached to a Hamilton microregulation syringe (Hamilton, Reno, NV). The injection volume of aggregated Aβ-type peptide or phosphate buffered saline (PBS) (control solution) was 1 microliter. Following injection, progressive neurodegeneration was allowed to develop for seven days before mice were evaluated for pathology or behavioral impairment. Aggregated Aβ-type peptides formed at the injection site were confirmed by immunohistochemistry of the brain.

The spatial learning ability of rats was assessed with the Morris water maze learning task. Animals were administered two sessions per day (one in the morning and one in the afternoon) with four tests per session. A total of six sessions were administered to assess animals. In each of the four tests, the animals were randomly placed in four different starting positions equally spaced around the perimeter of a tank filled with water (which was clouded by adding powdered milk) . They were then allowed to search for hidden platforms beneath the surface of the pool. If an animal cannot find the platform after 120 seconds, it is directed to the platform. After climbing onto the platform, the animals were allowed to stay for 20 seconds. The time required for each animal to find the platform was recorded as the escape latency.

Mice administered Aβ-type peptides were tested on a Moschuck water maze spatial learning task and their performance was compared to that of control mice injected with PBS alone. Mice given Aβ-type peptides performed significantly worse than control mice, as evidenced by significantly higher escape latencies.

Next, the mice administered with the Aβ-type peptide were divided into a G-CSF group and a control group. The mice in the G-CSF group were subcutaneously injected with recombinant human granulocyte colony-stimulating factor (Amgen Biologicals) at a dose of 50 μg/kg once a day for five days. In contrast, mice in the control group were subcutaneously injected with PBS. Afterwards, mice from both groups were tested on a water maze task and their performance was compared to mice given only granulocyte colony-stimulating factor (G-CSF) or only PBS.

In this task, mice given Aβ-peptides in the G-CSF group performed significantly better than mice given Aβ-peptides in the control group, which can be compared with mice given only granulocyte colony-stimulating factor or only PBS. Evidence of escape latency.

Consistent with the behavioral restoration of granulocyte colony-stimulating factor, it has been found that neurogenesis in the cerebral cortex and hippocampus (by As assessed by the co-labeling of newborn neurons by BrdU (a marker of cell proliferation) and MAP2 (a neuron-specific marker)) was higher than that in mice given Aβ-type peptides and only PBS.

These studies indicate that systemic administration of granulocyte colony-stimulating factor can improve the behavioral deficit in a mouse model of Alzheimer's disease, which is caused by the accumulation of Aβ by intracerebral injection and the accumulation of Aβ in the injection area. Stimulates increased neuronal proliferation.

Example 2

Long-lasting effects of granulocyte colony-stimulating factor

In order to test whether granulocyte colony-stimulating factor (G-CSF) can have a long-term therapeutic effect, the cognitive ability of Tg2576 mice was analyzed 3 months after treatment. To this end, 10 12-month-old mice were divided into two groups and tested with a water maze task as described above before and 3 months after subcutaneous injection of PBS and granulocyte colony-stimulating factor (G-CSF), respectively. As shown in Figure 1, the average latency of Tg2576 mice treated with PBS (3 months after Tg2576 injected with PBS) and not treated with PBS (Tg2576 injected with PBS control) was generally high. Clearly, however, granulocyte colony-stimulating factor-treated mice had significantly better learning/memory abilities, even 3 months after treatment (Tg2576 injected with G-CSF 3 months later vs Tg2576 administered with G-CSF injection control comparison). These data demonstrate that treatment with granulocyte colony stimulating factor produces long-lasting effects on cognitive restoration in Tg2576AD mice.

other embodiments

All the features disclosed in this specification can be combined in any way. Any feature disclosed in this specification may be replaced by an alternative feature serving the same, equivalent or similar purpose. For example, even without direct administration of a G-CSFR agent, the level of G-CSF in a subject suffering from progressive neurodegeneration can be increased by stimulating endogenous production, for example, by administering a G-CSFR agent to the subject's A1 gland. Glycine receptor agents (eg, US Patent No. 6,790,839). Indeed, the use of these compositions is also within the scope of the present invention.

From the above, those skilled in the art can easily ascertain the basic features of the present invention, and change and modify the present invention without departing from the spirit and scope of the present invention, making it suitable for various uses and situations. Accordingly, other embodiments are also contemplated.

sequence listing

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Claims (21)

1. A pharmaceutical composition for treating progressive neurodegeneration or inhibiting the occurrence of progressive neurodegeneration in high-risk subjects, characterized in that it contains at least an effective amount of granulocyte colony-stimulating factor receptor agent, thereby enabling hematopoiesis Stem cells move from the bone marrow to the peripheral blood. 2. The pharmaceutical composition according to claim 1, wherein the granulocyte colony-stimulating factor receptor agent comprises a G-CSF sequence variant that is at least 70% identical to human G-CSF. 3. The pharmaceutical composition according to claim 1, characterized in that the granulocyte colony-stimulating factor receptor agent comprises chemically modified mammalian G-CSF. 4. The pharmaceutical composition according to claim 1, characterized in that the granulocyte colony-stimulating factor receptor agent comprises a monoclonal antibody or an antibody-derived molecule capable of engaging and activating the granulocyte colony-stimulating factor receptor. 5. The pharmaceutical composition according to claim 1, characterized in that the affinity of the granulocyte colony stimulating factor receptor agent for the granulocyte colony stimulating factor receptor is at least one tenth of the affinity of G-CSF. 6. The pharmaceutical composition according to claim 1, wherein the 50% effective concentration of the granulocyte colony-stimulating factor receptor agent is at least about ten times that of G-CSF at 50% of the granulocyte colony-stimulating factor receptor agent effective concentration. 7. The pharmaceutical composition according to claim 1, wherein the progressive neurodegenerative disease is Alzheimer's disease, Parkinson's disease, Huntington's disease, Lewy body dementia or Pick's disease. 8. The pharmaceutical composition according to claim 1, wherein the progressive neurodegenerative disease is Alzheimer's disease. 9. The pharmaceutical composition according to claim 1, characterized in that the progressive neurodegenerative disease is Alzheimer's disease with reduced cognitive ability. 10. The pharmaceutical composition according to claim 9, wherein the cognitive ability is learning or memory. 11. The pharmaceutical composition according to claim 1, wherein the progressive neurodegeneration is caused by degeneration of hippocampal or cortical neurons. 12. The pharmaceutical composition according to claim 1, characterized in that the pharmaceutical composition has prolonged efficacy. 13. Use of a granulocyte colony-stimulating factor receptor agent or a pharmaceutical composition thereof in the manufacture of a drug for treating progressive neurodegeneration or inhibiting the occurrence of progressive neurodegeneration in high-risk subjects. 14. A method for selecting a highly effective granulocyte colony-stimulating factor receptor agent for the treatment or prevention of progressive neurodegeneration, characterized in that the method at least comprises: systemically administering a granulocyte colony-stimulating factor receptor agent to a non-human test mammal with progressive neurodegeneration; measuring the performance of the test mammal on a behavioral task; Compared to a control group of mammals administered with a granulocyte colony-stimulating factor receptor agent, the test mammals which performed better showed a high efficacy of the granulocyte colony-stimulating factor receptor agent for treating the degenerative disease. 15. The method of claim 14, wherein the progressive neurodegeneration is induced in the test mammal and the control mammal. 16. The method of claim 14, wherein the progressive neurodegeneration impairs learning or memory. 17. The method according to claim 14, wherein the progressive neurodegeneration is induced by administering amyloid-beta aggregated to the test mammal and the control mammal. 18. The method of claim 14, wherein the progressive neurodegeneration is caused by hippocampal or cortical neurodegeneration. 19. The method of claim 14, wherein the test mammal and the control mammal are biotechnologically produced. 20. The method of claim 14, wherein the test mammal and the control mammal are rodents. 21. The method of claim 14, wherein the test mammal is a mouse.