Sphingosine-1-phosphate receptor (S1PR) modulators for use in the treatment of patients suffering from dementia of the Alzheimer's type

Abstract

The present invention relates to sphingosine-1-phosphate receptor (S1PR) modulators for use in the treatment of patients suffering from Alzheimer's dementia.

Description

[Technical field]

[0001] The present invention relates to sphingosine-1-phosphate receptor (S1PR) modulators for use in the treatment of patients suffering from Alzheimer's dementia. [Background technology]

[0002] (background) Dementia is one of the greatest global challenges in health and social care in the 21st century. It occurs mainly in people over 65 years of age. Currently, around 50 million people worldwide live with dementia, and this number is predicted to triple by 2050. Global dementia-related costs in 2015 exceeded 800 billion euros per year, and this figure will continue to rise as the number of people living with dementia increases.

[0003] Alzheimer's disease (AD) is the most common form of dementia (approximately 60%), characterized by a progressive decline in cognitive function. Pathologically, AD is characterized by amyloid plaques and neurofibrillary tangles in the brain, accompanied by loss of synapses and neurons, leading to cognitive impairment and, ultimately, dementia. Although lifestyle choices such as exercise or a healthy diet may delay the onset of the disease, more than 30 years of dementia research have only recently led to the discovery of a single drug (aducanumab, FDA approved in 2021) that is used to treat the cause of dementia in AD patients.

[0004] Increasing evidence suggests that the pathogenesis of AD is not limited to neurons but involves a strong interaction with immune mechanisms in the brain. Misfolded and aggregated proteins bind to pattern recognition receptors on microglia and astroglia, triggering an innate immune response characterized by the release of inflammatory mediators, which contribute to disease progression and severity. This inflammatory response is also found in approximately 40% of dementia patients who, although not clearly classified as AD patients, exhibit similar synaptic dysfunction and therefore would also benefit from treatments addressing neuroinflammation. Thus, therapies focused on reducing neuroinflammatory signaling are among the most promising interventions to ameliorate AD-related impairments, as well as those observed in other types of dementia (e.g., vascular dementia, mixed AD and vascular dementia, frontotemporal dementia, and dementia with Lewy bodies). Thus, repurposing FDA-approved anti-inflammatory drugs to treat AD and other types of dementia may provide important advantages in rapidly developing effective AD / dementia therapeutics.

[0005] Fingolimod (FTY720, Gilenya®) is a drug approved (FDA and EMA) for the treatment of relapsing multiple sclerosis (RMS) since 2011. In target tissues, it is converted to fingolimod-phosphate, a potent modulator of sphingosine-1-phosphate receptors (S1PR1-5). Sphingosine-1-phosphate receptors are a family of seven helical transmembrane G protein-coupled receptors that recognize and bind extracellular sphingosine-1-phosphate and affect cellular processes. They are divided into five subtypes: S1PR1, S1PR2, S1PR3, S1PR4, and S1PR5. In the immune system, fingolimod-induced S1PR receptor modulation promotes the retention of T cells in lymph nodes, thereby reducing the infiltration of autoreactive lymphocytes into the central nervous system, where they attack the protective sheath that covers nerve fibers (myelin), causing permanent damage and / or deterioration of the nerves.

[0006] At present, there is no known cure for Alzheimer's dementia, especially when the disease has not yet begun but is already in its terminal stages.

[0007] The present invention is based on the surprising discovery that treatment with sphingosine-1-phosphate receptor modulators (such as fingolimod, FTY720) can stop the progression of synaptic loss and memory impairment in late AD.More surprising is the discovery that treatment with S1PR modulators is effective in reversing AD.S1PR modulators can also be used in combination therapy.

[0008] (Summary of the invention) In a first aspect, the present invention relates to a sphingosine-1-phosphate receptor (S1PR) modulator for use in treating patients suffering from Alzheimer's dementia. The S1PR modulator may be selected from the group consisting of fingolimod (FTY720), siponimod (BAF312), ozanimod (RPC1063), seralifimdo (ONO-4641), GSK2018682, ponesimod (ACT128800), and amiselimod (MT-1303).

[0009] In a second aspect, the present invention relates to a combination for use in the treatment of a patient suffering from Alzheimer's dementia, the combination comprising: (i) an S1PR modulator, and (ii) Contains other therapeutic substances.

[0010] The other therapeutic agent may be selected from the group consisting of aducanumab, lecanemab, gantenerumab, riluzole, donepezil, fluoxetine, citalopram, methylene blue, curcumin, lithium chloride, roscovitine, memantine, sodium selenate, pyridoxamine (vitamin B6), and 5-aminoimidazole-4-carboxamide-1-β-D-ribofuranoside (AICAR).

[0011] In a third aspect, the present invention relates to a pharmaceutical composition comprising a sphingosine-1-phosphate receptor (S1PR) modulator as defined in the first aspect or a combination as defined in the second aspect for use in the treatment of a patient suffering from dementia of the Alzheimer's type.

[0012] In a fourth aspect, the present invention relates to a method for treating Alzheimer's dementia comprising the steps of: (i) providing an S1PR modulator or a combination comprising an S1PR modulator and another therapeutic agent; (ii) administering to a patient suffering from Alzheimer's dementia a therapeutically effective amount of an S1PR modulator or a combination comprising an S1PR modulator and another therapeutic agent.

[0013] This summary of the invention does not necessarily describe every feature and / or every aspect of the invention. Other embodiments will become apparent upon consideration of the following detailed description. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0014] (Detailed Description) definition The present invention will now be described in more detail with reference to the drawings, in which: However, the specific embodiments, examples, or results of the present invention described are intended to be illustrative only and should not be construed in any way as limiting the scope of the present invention as set forth by the appended claims.

[0015] It is to be understood that the present invention is not limited to the specific methodology, protocols, and reagents described herein, which may vary. It is also to be understood that the terms used herein are for the purpose of describing specific embodiments only, and are not intended to limit the scope of the present invention, which is limited only by the scope of the appended claims. Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art.

[0016] Each document cited in this specification (including all patents, patent applications, scientific publications, manufacturer's specifications, instructions, etc.), whether stated above or below, is incorporated herein by reference in its entirety. In the event of a conflict between a definition or teaching of such an incorporated reference and a definition or teaching set forth in this specification, the body of the specification shall control.

[0017] In the present invention (particularly in the context of the claims), the term "comprising" or its variant "comprise(s)" is to be construed as an open-ended term or a non-exclusive inclusion (i.e., meaning "including, but not limited to"), respectively, unless otherwise specified.

[0018] The terms "a," "an," and "the" as used herein in the context of describing the invention (particularly in the context of the claims) shall be construed as including at least one element or component, respectively, and shall be construed as including both the singular and the plural, unless otherwise stated herein or clearly contradicted by context.

[0019] Further, unless expressly stated to the contrary, the term "or" refers to an inclusive "or" rather than an exclusive "or" (i.e., meaning "and / or").

[0020] As used herein, all numerical values, whether expressly stated or not, are deemed to be modified by the term "about." The recitation of ranges of values ​​herein is intended to serve as a shorthand method of referring individually to each individual value falling within the range, unless otherwise stated herein, and each individual value is incorporated herein as if it were individually set forth herein.

[0021] The use of the terms "for example," "eg," "such as," or variations thereof are intended only to more clearly describe the invention and do not limit the scope of the invention unless specifically stated otherwise. These terms should be interpreted to mean "without limitation" or "without limitation."

[0022] The term "dementia" as used herein is a general term referring to a decline in mental abilities severe enough to interfere with daily life. Dementia refers to a set of symptoms associated with a decline in memory, reasoning, or other thinking skills. There are many different types of dementia, and many different medical conditions that cause them. Mixed dementia is a condition in which brain changes from more than one type of dementia occur simultaneously. Alzheimer's disease is the most common cause of dementia, accounting for 60-80% of dementia cases (AD, or mixed AD + vascular dementia). Alzheimer's disease is a specific disease. Dementia is not.

[0023] The term "Alzheimer's disease (AD)" as used herein refers to a neurodegenerative disease. It is the most common form of dementia. Alzheimer's disease is characterized by loss of neurons and synapses in the cerebral cortex and certain subcortical regions, causing significant degeneration in these regions. In Alzheimer's disease, accumulation of abnormally folded Abeta and tau proteins in affected tissues leads to protein misfolding and aggregation in the brain (the formation of so-called "plaques"). The most common early symptom is difficulty remembering recent events (short-term memory loss). As the disease progresses, symptoms may include speech impairment, disorientation, mood swings, loss of motivation, inability to control oneself, and behavioral problems. As the condition worsens, the individual often becomes withdrawn from family and society. Gradually, bodily functions are lost, eventually resulting in death.

[0024] As used herein, the term "Alzheimer's dementia" refers to a specific form of Alzheimer's disease.

[0025] Alzheimer's disease (AD) is the leading cause of dementia in older adults worldwide and occurs in familial and sporadic forms, the latter of which accounts for the majority of patients affected by the disease.

[0026] As used herein, the term "sporadic Alzheimer's dementia" refers to a multifactorial disease in which both genetic predisposition and environmental factors contribute to the development of the disease. The majority of AD dementia cases (>95%) belong to the sporadic type of the disease. Sporadic Alzheimer's disease can affect adults of any age, but usually begins after age 65.

[0027] As used herein, the term "familial Alzheimer's dementia" refers to a disease resulting from mutations in any of three genes, including amyloid precursor protein (APP), presenilin 1 (PS1), and presenilin 2 (PS2), which usually develops at a slightly younger age than sporadic cases and has a more aggressive course of progression. A minority of AD dementia cases (less than 5%) belong to familial Alzheimer's dementia.

[0028] The term "sphingosine-1-phosphate (S1P)" as used herein refers to a signaling molecule involved in, among other things, lymphocyte migration, brain and heart development, vascular permeability, and the regulation of vascular and bronchial tone. In this regard, S1P acts through a series of membrane-bound S1P receptors, in particular S1P receptor subtypes (S1PR1, 2, 3, 4, 5) that display various organ- and cell-specific expression patterns and have distinct functions.

[0029] As used herein, the term "sphingosine-1-phosphate receptor (S1PR)" refers to the receptor to which S1P binds.

[0030] In biochemistry and pharmacology, a "receptor modulator" is a general term for an endogenous or exogenous substance that binds to and modulates the activity of a specific cellular receptor, a protein structure that receives and transmits signals and causes some form of cellular response. Receptor modulators act on different parts of the receptor to modulate activity in a positive, negative, or neutral direction with different levels of effectiveness. These categories of receptor modulators include receptor agonists and receptor antagonists. In general, an agonist is a modulator (e.g., a drug) that binds to a receptor and produces a response similar to the intended (natural) binding ligand. An antagonist is a modulator (e.g., a drug) that binds to a receptor and stops the receptor from producing a cellular response.

[0031] The term "sphingosine-1-phosphate receptor (S1PR) modulator" as used herein refers to a molecule that binds to the S1P receptor, for example on lymphocytes, resulting in internalization of the receptor. Sensitivity to the S1P gradient is then lost, and lymphocytes are believed to remain in the lymph nodes. The number of circulating cells is reduced, and migration of inflammatory cells into the central nervous system is reduced. In addition, direct effects of S1PR modulators on the blood-brain barrier, microglia, astrocytes, and oligodendrocytes may also be relevant.

[0032] The S1PR modulator preferably used in the present invention is selected from the group consisting of fingolimod (FTY720), siponimod (BAF312), ozanimod (RPC1063), seralifimod (ONO-4641), GSK2018682, ponesimod (ACT128800), and amiselimod (MT-1303). More preferably, the S1PR modulator is selected from the group consisting of fingolimod (FTY720), ozanimod (RPC1063), siponimod (BAF312), and ponesimod (ACT128800).

[0033] The term "patient" as used herein refers to any individual who may be administered the S1PR modulator or a combination comprising the S1PR modulator and other therapeutic substances described herein. In particular, the term "subject" as used herein refers to any individual who may benefit from treatment with the S1PR modulator or a combination comprising the S1PR modulator and other therapeutic substances described herein. Specifically, the term "patient" in the context of the present invention refers to a subject who is undergoing, will undergo, or has undergone medical treatment for a disease or condition, i.e., Alzheimer's dementia. Preferably, the Alzheimer's dementia is sporadic Alzheimer's dementia or familial Alzheimer's dementia.

[0034] A patient may be, for example, a vertebrate such as a human, dog, cat, sheep, goat, cow, horse, camel, or pig. It is particularly preferred that the "patient" is a human.

[0035] As used herein, the term "treatment", particularly "therapy", refers to any therapy that improves the health and / or extends (increases) the lifespan of a subject suffering from a disease. The therapy can eliminate the disease in a subject, prevent or slow the progression of the disease in a subject, inhibit the progression of the disease in a subject, reduce the severity of symptoms in a subject suffering from a disease, and / or reduce recurrence in a subject currently suffering from or previously suffering from a disease.

[0036] As used herein, the expressions "is for administration" and "is to be administered" have the same meaning as "prepared to be administered". In other words, the statement that an active compound is "for administration" should be understood to mean that the active compound is formulated and dosed so that the active compound is in a state where it can exert its therapeutic effect. In the context of the present invention, the S1PR modulator or a composition comprising an S1PR modulator described herein can be prepared for administration.

[0037] In the present invention, the S1PR modulator, or a composition comprising it, is generally administered in a "therapeutically (pharmaceutical) effective" amount. The term "therapeutically (pharmaceutical) effective" amount as used herein generally refers to an amount of drug that achieves a desired response or a desired effect, either alone or in combination with further doses. In the case of the treatment of a particular disease, the desired response is preferably related to the inhibition of the progression of the disease. This includes slowing the progression of the disease, in particular arresting or reversing the progression of the disease. In the treatment of a disease, the desired response may be slowing or preventing the onset of the disease. The "therapeutically (pharmaceutical) effective" amount of a drug generally depends on the condition of the patient being treated, the severity of the disease, the individual parameters of the patient, including age, physiological state, size, and weight, the duration of treatment, the type of concomitant treatment (if any), the specific route of administration, and similar factors. If the patient does not respond adequately to the initial dose, a higher dose (or a substantially higher dose achieved by a different, more localized route of administration) may be used.

[0038] The pharmaceutical compositions described herein preferably further comprise one or more pharma- ceutically acceptable excipients, diluents, and / or carriers.

[0039] The term "excipient" as used herein is intended to refer to any substance in a pharmaceutical composition that is not an active ingredient, such as a binder, lubricant, thickener, surfactant, preservative, emulsifier, buffer, flavoring agent, or coloring agent.

[0040] As used herein, the term "diluent" refers to a diluent and / or thinning agent. Additionally, the term "diluent" includes a solution, a suspension (e.g., a liquid or solid suspension), and / or a medium.

[0041] The term "carrier" as used herein refers to one or more compatible solid or liquid fillers, suitable for administration, for example, to humans. The term "carrier" refers to a natural or synthetic organic or inorganic component with which the active ingredient is combined to facilitate application of the active ingredient or penetration of the active ingredient into the intended site of action. Preferably, the carrier component is a sterile liquid, such as water or oil, including those of mineral, animal, or vegetable origin, such as peanut oil, soybean oil, sesame oil, sunflower oil, and the like. Salt solutions and aqueous dextrose and glycerin solutions can also be used as aqueous carrier compounds. A carrier compound that improves or promotes penetration into the skin in topical applications is dimethyl sulfoxide (DMSO). Another preferred carrier consists of layered double hydroxide (LDH) nanoparticles. For example, such LDH nanoparticles are in the form of [Mg3Al(OH)8](CH3CHOHCOO), which can be obtained, for example, by reacting Mg(lactate)2·3H2O with Al(lactate)3 at 45-65 °C with pH controlled with NaOH, and can be protected from CO2 and carbonate. Circular RNA can be inserted into the LDH nanoparticles and administered as LDH nanoparticles or co-administered with VLPs.

[0042] Pharmaceutical carriers, diluents, and / or excipients may be selected taking into consideration the intended route of administration and standard pharmaceutical practice. The pharmaceutical compositions of the present invention may comprise any suitable binder(s), lubricant(s), suspending agent(s), coating agent(s), and / or solubilizing agent(s) as, or in addition to, the carrier(s), excipient(s) or diluent(s). Examples of suitable binders include starch, gelatin, natural sugars such as glucose, lactose, sucrose, trehalose, corn sweeteners, natural and synthetic gums such as acacia, tragacanth, or sodium alginate, carboxymethylcellulose, and polyethylene glycol. Examples of suitable lubricants include sodium oleate, sodium stearate, magnesium stearate, sodium benzoate, sodium acetate, sodium chloride, and the like. Preservatives, stabilizers, dyes, and even flavorings may also be provided in the pharmaceutical composition. Examples of preservatives include sodium benzoate, sorbic acid, and esters of p-hydroxybenzoic acid. Antioxidants and suspending agents may also be used.

[0043] No language in the specification should be construed as indicating any non-claimed element as essential to the practice of the invention.

[0044] Embodiment The present invention is based on the surprising discovery that treatment with sphingosine-1-phosphate receptor modulators (such as fingolimod, FTY720) can stop the progression of synaptic loss and memory impairment in late AD.More surprising is the discovery that treatment with S1PR modulators is effective in reversing AD.S1PR modulators can also be used in combination therapy.

[0045] Thus, in a first aspect, the present invention relates to a sphingosine-1-phosphate receptor (S1PR) modulator for use in the treatment of a patient suffering from dementia of the Alzheimer's type.

[0046] The S1PR modulator used in the present invention may be selected from the group consisting of fingolimod (FTY720), siponimod (BAF312), ozanimod (RPC1063), seralifimod (ONO-4641), GSK2018682, ponesimod (ACT128800), and amiselimod (MT-1303). Fingolimod (FTY720), ozanimod (RPC1063), siponimod (BAF312), or ponesimod (ACT128800) are preferred S1PR modulators. Thus, in a preferred embodiment, the sphingosine-1-phosphate receptor (S1PR) modulator for use in the treatment of patients suffering from Alzheimer's dementia is fingolimod (FTY720), ozanimod (RPC1063), siponimod (BAF312), or ponesimod (ACT128800).

[0047] Fingolimod (FTY720, Gilenya®) has the following chemical formula: [ka]

[0048] Siponimod (BAF312) has the following chemical formula: [ka]

[0049] Ozanimod (RPC1063, trade name Zeposia®) has the following chemical formula: [ka]

[0050] Seralifimdo (ONO-4641) has the following chemical formula: [ka]

[0051] GSK2018682 has the following chemical formula: [ka]

[0052] Ponesimod (ACT128800) has the following chemical formula: [ka]

[0053] Amicelimod (MT-1303) has the following chemical formula: [ka]

[0054] The above-mentioned S1PR modulators have previously been used as therapeutic agents for multiple sclerosis or inflammatory bowel disease.

[0055] Those skilled in the art understand that certain S1PR modulators may have different optical isomers as a result of one or more asymmetric or chiral carbon atoms.In addition, some S1PR modulators may show polymorphism.It is also clear that the pharmaceutically acceptable salt, ester, solvate or hydrate of S1PR modulators, as well as the prodrugs that can be converted to S1PR modulators in vivo, can also be used in the present invention.

[0056] Examples of pharma- ceutically acceptable salts of the above-mentioned S1PR modulators are salts of sufficiently basic S1PR modulators with physiologically acceptable mineral acids, such as hydrochloric acid, sulfuric acid, or phosphoric acid, or salts of organic acids, such as acetic acid, lactic acid, citric acid, succinic acid, fumaric acid, maleic acid, or salicylic acid. In addition, sufficiently acidic S1PR modulators can form alkali metal or alkaline earth metal salts, such as sodium salts, potassium salts, lithium salts, calcium salts, or magnesium salts, ammonium salts, or salts of organic bases, such as methylamine salts, dimethylamine salts, trimethylamine salts, triethylamine salts, ethylenediamine salts, ethanolamine salts, choline hydroxide salts, piperidine salts, morpholine salts, tris(2-hydroxyethyl)amine salts, lysine salts, or arginine salts.

[0057] A pharma- ceutically acceptable ester of the S1PR modulator is an ester that can be hydrolyzed by esterase enzymes in the human body to yield the S1PR modulator having the above formula.

[0058] The pharma- ceutically acceptable solvates of the S1PR modulators are complex compounds (adducts) formed by the interaction of molecules of a solvent with molecules of the S1PR modulators. Hydrates are solvates in which the solvent is water.

[0059] According to the present invention, sphingosine-1-phosphate receptor (S1PR) modulators (such as fingolimod) may be used to treat patients suffering from Alzheimer's dementia, wherein the patient is about 40 years of age or older.

[0060] The Alzheimer's dementia to be treated can be sporadic Alzheimer's dementia or familial Alzheimer's dementia. Familial Alzheimer's disease is a rare special form (1-2%) of classical Alzheimer's disease, and the age of onset of the disease can be younger, starting at about age 40, whereas sporadic Alzheimer's disease usually begins after age 60.

[0061] Thus, according to the present invention, sphingosine-1-phosphate receptor (S1PR) modulators (such as fingolimod) may be used to treat patients suffering from sporadic Alzheimer's dementia, where the patient may be about 60 years of age or older, or in the case of patients suffering from familial Alzheimer's dementia, the patient may be about 40 years of age or older.

[0062] Thus, in a more preferred embodiment, the sphingosine-1-phosphate receptor (S1PR) modulator for use in the treatment of a patient suffering from dementia of the Alzheimer's type is fingolimod (FTY720), ozanimod (RPC1063), siponimod (BAF312), or ponesimod (ACT128800), wherein the dementia of the Alzheimer's type is sporadic dementia of the Alzheimer's type and the patient is about 60 years of age or older.

[0063] In another more preferred embodiment, the sphingosine-1-phosphate receptor (S1PR) modulator for use in the treatment of a patient suffering from dementia of the Alzheimer's type is fingolimod (FTY720), ozanimod (RPC1063), siponimod (BAF312), or ponesimod (ACT128800), wherein the dementia of the Alzheimer's type is familial dementia of the Alzheimer's type and the patient is about 40 years of age or older.

[0064] Those skilled in the art will appreciate that the above ages of Alzheimer's disease patients are only very approximate as boundaries of disease onset may overlap.

[0065] In one embodiment of the invention, the patient to whom a sphingosine-1-phosphate receptor (S1PR) modulator (such as fingolimod) is administered has undergone or is undergoing behavioral therapy, physical exercise training, reality orientation training, physical therapy, occupational therapy, or cognitive training (memory training), or a combination thereof.

[0066] According to the present invention, S1PR modulators (such as fingolimod) can be used to reverse Alzheimer's dementia, which is a very surprising discovery of the present invention.

[0067] In the present invention, the administration route of the S1PR modulator is not particularly limited, and may be either enteral or parenteral. Examples include intraperitoneal administration or oral administration.

[0068] Those skilled in the art will appreciate that the S1PR modulators may be administered as is or in the form of a pharmaceutical composition or formulation that contains the S1PR modulator as an active agent and, optionally, pharma- ceutically acceptable excipients (e.g., carriers, fillers, diluents, absorbents, binders, adjuvants, etc.) commonly used in herbal medicines.

[0069] For oral administration, the S1PR modulators can be formulated, for example, as tablets (including effervescent tablets, sustained release tablets, controlled release tablets, or enteric coated tablets), sugar-coated tablets, pills, granules, powders, gels, semisolids, capsules (including soft and hard capsules, sustained release capsules, controlled release capsules, or enteric coated capsules). The above oral dosage forms can be prepared according to standard galenic procedures, for example, using pharmaceutically acceptable carriers well known in the art. Pharmaceutically acceptable carriers include fillers, absorbents, wetting agents, binders, disintegrants, lubricants, etc. Fillers include starch, lactose, mannitol, microcrystalline cellulose, etc. Absorbents include calcium sulfate, calcium hydrogen phosphate, calcium carbonate, etc. Wetting agents include water, ethanol, etc. Binders include hydroxypropylmethylcellulose, polyvinylpyrrolidone (povidone, INN), microcrystalline cellulose, etc. Disintegrants include croscarmellose sodium, crospovidone, surfactants, low-substituted hydroxypropylcellulose, etc. Lubricants include magnesium stearate, talc powder, polyethylene glycol, sodium dodecyl sulfate, colloidal silicon dioxide, talc powder, etc. Liquids (such as aqueous or oily solutions), emulsions, suspensions, or syrups are also suitable for oral administration.

[0070] For intraperitoneal administration, the S1PR modulator may be formulated, for example, as an injectable solution, emulsion, or suspension. A suitable solvent is, for example, 3% dimethylsulfoxide (DMSO).

[0071] Pharmaceutical compositions or formulations containing S1PR modulators may also contain additives used in herbal medicines, such as preservatives, stabilizers (e.g., UV stabilizers), emulsifiers, sweeteners, flavors, colorants, salts for changing osmotic pressure, buffers, antioxidants, and the like.

[0072] According to the present invention, an S1PR modulator (such as fingolimod) for the treatment of Alzheimer's disease may be administered in an amount of about 0.008 to about 5 mg, for example about 0.03 mg to about 5 mg, of S1PR modulator per kg of body weight per 1 to 2 days. Examples of suitable amounts within this range are 0.008, 0.009, 0.01, 0.02, 0.03, 0.04, 0.05, 0.06, 0.07, 0.08, 0.09, 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2, 2.1, 2.2, 2.3, 2.4, 2.5, 3, 3.5, 4, 4.5, and 5 mg of S1PR modulator (such as fingolimod) per kg of body weight per 1-2 days.

[0073] Fingolimod (FTY720) can be administered, for example, in an amount of about 0.008 mg (equivalent to a daily dose of 0.5 mg for a multiple sclerosis patient) to about 3 mg of fingolimod per kg of body weight per 1-2 days, for example, in an amount of about 0.2 mg to about 3 mg of fingolimod per kg of body weight per 1-2 days, or in an amount of about 0.2 mg to about 1 mg of fingolimod per kg of body weight per 1-2 days. Examples of suitable amounts within this range are 0.008, 0.009, 0.01, 0.02, 0.03, 0.04, 0.05, 0.06, 0.07, 0.08, 0.09, 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2, 2.1, 2.2, 2.3, 2.4, 2.5, 2.6, 2.7, 2.8, 2.9, and 3 mg of fingolimod per kg of body weight per 1 to 2 days.

[0074] Ozanimod (RPC1063) can be administered, for example, in the same amounts as fingolimod (FTY720), for example, in an amount of about 0.008 mg (equivalent to a daily dose of 0.5 mg for a multiple sclerosis patient) to about 3 mg of ozanimod per kg of body weight per 1-2 days, for example, in an amount of about 0.2 mg to about 3 mg of ozanimod per kg of body weight per 1-2 days, or in an amount of about 0.2 mg to about 1 mg of ozanimod per kg of body weight per 1-2 days. Examples of suitable amounts within this range are 0.008, 0.009, 0.01, 0.02, 0.03, 0.04, 0.05, 0.06, 0.07, 0.08, 0.09, 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2, 2.1, 2.2, 2.3, 2.4, 2.5, 2.6, 2.7, 2.8, 2.9, and 3 mg of ozanimod per kg of body weight per 1 to 2 days.

[0075] Siponimod (BAF312) can be administered, for example, in an amount of about 0.008 mg to about 3 mg of siponimod per kg of body weight per 1-2 days, for example, in an amount of about 0.2 mg to about 3 mg of siponimod per kg of body weight per 1-2 days, or in an amount of about 0.2 mg to about 1 mg of siponimod per kg of body weight per 1-2 days. Examples of suitable amounts within this range are 0.008, 0.009, 0.01, 0.02, 0.03, 0.04, 0.05, 0.06, 0.07, 0.08, 0.09, 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2, 2.1, 2.2, 2.3, 2.4, 2.5, 2.6, 2.7, 2.8, 2.9, and 3 mg of siponimod per kg of body weight per 1 to 2 days.

[0076] Ponesimod (ACT128800) can be administered, for example, in an amount of about 0.008 mg to about 3 mg of ponesimod per kg of body weight per 1-2 days, for example, in an amount of about 0.2 mg to about 3 mg of ponesimod per kg of body weight per 1-2 days, or in an amount of about 0.2 mg to about 1 mg of ponesimod per kg of body weight per 1-2 days. Examples of suitable amounts within this range are 0.008, 0.009, 0.01, 0.02, 0.03, 0.04, 0.05, 0.06, 0.07, 0.08, 0.09, 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2, 2.1, 2.2, 2.3, 2.4, 2.5, 2.6, 2.7, 2.8, 2.9, and 3 mg of ponesimod per kg of body weight per 1 to 2 days.

[0077] Those skilled in the art will recognize that other dosages and / or durations of administration may be appropriate or necessary, depending on the circumstances of an individual patient.

[0078] Thus, in an even more preferred embodiment, the sphingosine-1-phosphate receptor (S1PR) modulator for use in the treatment of a patient suffering from dementia of the Alzheimer's type is fingolimod (FTY720), ozanimod (RPC1063), siponimod (BAF312), or ponesimod (ACT128800), wherein the dementia of the Alzheimer's type is sporadic dementia of the Alzheimer's type, and the patient is about 60 years of age or older; Fingolimod is administered in an amount of about 0.008 to about 5 mg, for example about 0.03 mg to about 5 mg, of fingolimod per kg of body weight per 1 to 2 days; Ozanimod is administered in an amount of about 0.008 to about 5 mg, e.g., about 0.03 mg to about 5 mg, of ozanimod per kg of body weight per 1 to 2 days, Siponimod is administered in an amount of about 0.008 to about 5 mg, e.g., about 0.03 mg to about 5 mg, of siponimod per kg of body weight per 1 to 2 days; or Ponesimod is administered in an amount of about 0.008 to about 5 mg, for example, about 0.03 mg to about 5 mg, of ponesimod per kg of body weight per 1 to 2 days.

[0079] In another even more preferred embodiment, the sphingosine-1-phosphate receptor (S1PR) modulator for use in the treatment of a patient suffering from dementia of the Alzheimer's type is fingolimod (FTY720), ozanimod (RPC1063), siponimod (BAF312), or ponesimod (ACT128800), wherein the dementia of the Alzheimer's type is familial dementia of the Alzheimer's type, and the patient is about 40 years of age or older; Fingolimod is administered in an amount of about 0.008 to about 5 mg, for example about 0.03 mg to about 5 mg, of fingolimod per kg of body weight per 1 to 2 days; Ozanimod is administered in an amount of about 0.008 to about 5 mg, e.g., about 0.03 mg to about 5 mg, of ozanimod per kg of body weight per 1 to 2 days, Siponimod is administered in an amount of about 0.008 to about 5 mg, e.g., about 0.03 mg to about 5 mg, of siponimod per kg of body weight per 1 to 2 days; or Ponesimod is administered in an amount of about 0.008 to about 5 mg, for example, about 0.03 mg to about 5 mg, of ponesimod per kg of body weight per 1 to 2 days.

[0080] For example, ozanimod (RPC1063) is available as capsules of various strengths and should be taken once daily. To reduce the risk of side effects, the dose may be gradually increased at the beginning of treatment or after treatment interruption. The starting dose may be one 0.23 mg capsule daily for the first 4 days, one 0.46 mg capsule daily for the next 3 days (days 5, 6, and 7), and one 0.92 mg capsule daily from day 8 onwards.

[0081] According to the present invention, the administration of the S1PR modulator can be carried out, for example, for a period of about 1 month to 24 months, preferably for a period of about 1 month to 12 months, for example, for about 1 month to 6 months, or for about 1 month to 2 months. However, those skilled in the art understand that other administration periods may be appropriate or necessary depending on the individual patient's circumstances. Repeated rhythmic application, such as application for 2 months (daily, or every other day, or once a week), then interrupted for 6 months, and then again for 2 months (with different rhythms, for example, once a week, every other day, daily, or with different FTY720 concentrations), or any other related scheme consisting of repeated treatment periods alternating with interruptions in treatment, is also possible.

[0082] In one embodiment of the invention, the patient to whom the S1PR modulator is administered may be a patient who has undergone or is undergoing behavioral therapy, physical exercise training, reality orientation training, physical therapy, occupational therapy, or cognitive training (memory training), or a combination thereof.

[0083] In another embodiment of the invention, the S1PR modulator may be used in combination with an agent selected from the group consisting of aducanumab, lecanemab, gantenerumab, riluzole, donepezil, fluoxetine, citalopram, methylene blue, curcumin, lithium chloride, roscovitine, memantine, sodium selenate, pyridoxamine (vitamin B6), and 5-aminoimidazole-4-carboxamide-1-β-D-ribofuranoside (AICAR).

[0084] Aducanumab is an amyloid-β-targeting monoclonal antibody that received accelerated approval for the treatment of Alzheimer's disease in the United States in June 2021 under the name Aduhelm (Biogen). Lecanemab is another amyloid-β-targeting monoclonal antibody that was most recently approved by the U.S. Food and Drug Administration (FDA) for the treatment of Alzheimer's disease. Gantenerumab is also an amyloid-β-targeting monoclonal antibody that is currently under investigation.

[0085] Riluzole is approved in the United States for the treatment of amyotrophic lateral sclerosis (ALS) and has the chemical formula: [ka]

[0086] Donepezil was approved in the United States in 2006 for the treatment of mild, moderate, and severe dementia due to Alzheimer's disease and has the chemical formula: [ka]

[0087] Fluoxetine is an antidepressant sold under the brand names Prozac and Sarafem. It is on the World Health Organization's list of essential medicines and has the chemical formula: [ka]

[0088] Citalopram is an antidepressant sold under brand names such as Celexa. It is on the World Health Organization's list of essential medicines and has the chemical formula: [ka]

[0089] Methylene blue (methylthionium chloride) is a salt of a thiazine dye. It is a tau protein aggregation inhibitor, stabilizes the physiological normal function of mitochondria, and prevents the formation of toxic oxygen radicals. Its chemical formula is: [ka]

[0090] Curcumin is a bright yellow chemical produced by the turmeric plant. It is a tau protein aggregation inhibitor and has the chemical formula (keto tautomer): [ka] Lithium chloride is a tau protein aggregation inhibitor.

[0091] Roscovitine (seliciclib, CYC202) is currently being investigated as a treatment for chronic inflammatory diseases. It is a tau protein aggregation inhibitor and has the chemical formula: [ka]

[0092] Memantine was approved for medical use in the United States in 2003 and is used to slow the progression of moderate to severe Alzheimer's disease. It is a tau protein aggregation inhibitor and has the chemical formula: [ka]

[0093] Sodium selenate is a tau protein aggregation inhibitor and has the chemical formula Na2SeO4.

[0094] Pyridoxamine is a form of vitamin B6. It stabilizes the physiological function of mitochondria and prevents the formation of toxic oxygen radicals. Its chemical formula is: [ka]

[0095] 5-Aminoimidazole-4-carboxamide-1-β-D-ribofuranoside (Acadesine, AICAR) is used in the treatment of acute lymphoblastic leukemia and has the chemical formula: [ka]

[0096] Those skilled in the art understand that certain of the above compounds may have different tautomeric forms and / or different optical isomers as a result of one or more asymmetric or chiral carbon atoms.In addition, some compounds may show polymorphism.It is also clear that the pharmaceutically acceptable salts, esters, solvates or hydrates of the above compounds, as well as the prodrugs that can be converted to the above compounds in vivo, can also be used in the present invention.

[0097] Examples of pharma- ceutically acceptable salts of the above compounds are salts of sufficiently basic compounds of the above formula with physiologically acceptable mineral acids, such as hydrochloric acid, sulfuric acid, or phosphoric acid, or with organic acids, such as acetic acid, lactic acid, citric acid, succinic acid, fumaric acid, maleic acid, or salicylic acid. Additionally, sufficiently acidic compounds of the above formula may form alkali metal or alkaline earth metal salts, such as sodium, potassium, lithium, calcium, or magnesium salts, ammonium salts, or salts of organic bases, such as methylamine, dimethylamine, trimethylamine, triethylamine, ethylenediamine, ethanolamine, choline hydroxide, piperidine, morpholine, tris(2-hydroxyethyl)amine, lysine, or arginine salts.

[0098] Pharmaceutically acceptable esters of the above compounds are esters of the above compounds which can be hydrolyzed by esterase enzymes in the human body to the compounds of the above formula.

[0099] Pharmaceutically acceptable solvates of the compounds are complex compounds (adducts) formed by the interaction of molecules of a solvent with molecules of the compound. Hydrates are solvates in which the solvent is water.

[0100] The present inventors demonstrated that administration of fingolimod significantly reduced the CD11c expression in the cortex of 15-month-old male AD mice. + / CD14 +We found that fingolimod reduced the increase in frequency and volume of aging / AD-related microglia (see Figures 8 and 9). + / CD14 + It is reasonable to speculate that sphingosine-1-phosphate receptor (S1PR) modulators, such as fingolimod, described herein are for use in treating patients suffering from Alzheimer's dementia, where fingolimod inhibits CD11c expression in the cortex of the patient. + / CD14 + Targeting aging / AD-associated microglial cells.

[0101] The first aspect of the present invention may alternatively be formulated as follows: Use of a sphingosine-1-phosphate receptor (S1PR) modulator in the manufacture of a medicament for the treatment of a patient suffering from Alzheimer's dementia. Additionally, the first aspect of the present invention may alternatively be formulated as follows: A method for treating Alzheimer's dementia, comprising administering to the patient a therapeutically effective amount of a sphingosine-1-phosphate receptor (S1PR) modulator comprising administering to the patient a therapeutically effective amount of a sphingosine-1-phosphate receptor (S1PR) modulator. (i) providing an S1PR modulator; (ii) administering to a patient suffering from Alzheimer's dementia a therapeutically effective amount of an S1PR modulator.

[0102] In a second aspect, the present invention relates to a combination for use in the treatment of a patient suffering from Alzheimer's dementia, the combination comprising: (i) an S1PR modulator, and (ii) Contains other therapeutic substances.

[0103] According to this aspect of the invention, the S1PR modulator may be selected from the group consisting of fingolimod (FTY720), siponimod (BAF312), ozanimod (RPC1063), seralifimdo (ONO-4641), GSK2018682, ponesimod (ACT128800), and amiselimod (MT-1303). Fingolimod (FTY720), ozanimod (RPC1063), siponimod (BAF312), or ponesimod (ACT128800) are preferred S1PR modulators. Thus, in a preferred embodiment, the combination for use in the treatment of a patient suffering from Alzheimer's dementia comprises (i) an S1PR modulator, and (ii) contains another therapeutic substance; wherein the sphingosine-1-phosphate receptor (S1PR) modulator is fingolimod (FTY720), ozanimod (RPC1063), siponimod (BAF312), or ponesimod (ACT128800).

[0104] Other therapeutic agents are also suitable for treating Alzheimer's dementia in a patient. In a more preferred embodiment, a combination for use in treating a patient suffering from Alzheimer's dementia comprising: (i) an S1PR modulator, and (ii) containing other therapeutic substances suitable for the treatment of Alzheimer's disease; wherein the sphingosine-1-phosphate receptor (S1PR) modulator is fingolimod (FTY720), ozanimod (RPC1063), siponimod (BAF312), or ponesimod (ACT128800), the Alzheimer's dementia is sporadic Alzheimer's dementia, and the patient is about 60 years of age or older.

[0105] In another more preferred embodiment, there is provided a combination for use in treating a patient suffering from Alzheimer's dementia, comprising: (i) an S1PR modulator, and (ii) containing other therapeutic substances suitable for the treatment of Alzheimer's disease; wherein the sphingosine-1-phosphate receptor (S1PR) modulator is fingolimod (FTY720), ozanimod (RPC1063), siponimod (BAF312), or ponesimod (ACT128800), the Alzheimer's dementia is familial Alzheimer's dementia, and the patient is about 40 years of age or older.

[0106] For other preferred embodiments of the S1PR modulators, please see the first aspect of the invention.

[0107] The other therapeutic agent may be selected from the group consisting of aducanumab, riluzole, donepezil, fluoxetine, citalopram, methylene blue, curcumin, lithium chloride, roscovitine, memantine, sodium selenate, pyridoxamine (vitamin B6), and 5-aminoimidazole-4-carboxamide-1-β-D-ribofuranoside (AICAR).

[0108] Preferred combinations of S1PR modulators with other therapeutic agents are as follows: -Fingolimod and fluoxetine -Ozanimod and fluoxetine -Siponimod and fluoxetine -Ponesimod and fluoxetine -Fingolimod and Citalopram -Ozanimod and Citalopram -Siponimod and Citalopram -Ponesimod and Citalopram -Fingolimod and AICAR -Ozanimod and AICAR -Siponimod and AICAR - PONESIMOD and AICAR -Fingolimod and sodium selenite -Ozanimod and sodium selenite -Siponimod and sodium selenite -Ponesimod and sodium selenite -Fingolimod and AICAR -Ozanimod and AICAR -Siponimod and AICAR - PONESIMOD and AICAR -Fingolimod and LiCl -Ozanimod and LiCl -Siponimod and LiCl -Ponesimod and LiCl -Fingolimod and lecanemab -Ozanimod and lecanemab -Siponimod and Lecanemab -Ponesimod and lecanemab -Fingolimod and gantenerumab -Ozanimod and gantenerumab -Siponimod and gantenerumab -Ponesimod and gantenerumab -Fingolimod and aducanumab -Ozanimod and aducanumab -Siponimod and aducanumab -Ponesimod and aducanumab

[0109] The components of the combination, i.e., the S1PR modulator and the other therapeutic agent, can be administered together or independently of each other (e.g., one at a time).

[0110] In an even more preferred embodiment, a combination for use in treating a patient suffering from Alzheimer's dementia comprising: (i) an S1PR modulator, and (ii) containing other therapeutic substances suitable for the treatment of Alzheimer's disease; wherein the sphingosine-1-phosphate receptor (S1PR) modulator is fingolimod (FTY720), ozanimod (RPC1063), siponimod (BAF312), or ponesimod (ACT128800), and the other therapeutic agent suitable for treating Alzheimer's dementia is selected from the group consisting of fluoxetine, citalopram, AICAR, sodium selenite, LiCl, lecanemab, and gantenerumab, and the Alzheimer's dementia is sporadic Alzheimer's dementia, and the patient is about 60 years of age or older.

[0111] In the above embodiment, Fingolimod is administered in an amount of about 0.008 to about 5 mg, e.g., about 0.03 mg to about 5 mg, of fingolimod per kg of body weight per 1 to 2 days; Ozanimod is particularly administered in an amount of about 0.008 to about 5 mg, e.g., about 0.03 mg to about 5 mg, of ozanimod per kg of body weight per 1 to 2 days; Siponimod is particularly administered in an amount of about 0.008 to about 5 mg, e.g., about 0.03 mg to about 5 mg, of siponimod per kg of body weight per 1 to 2 days, or Ponesimod is particularly administered in an amount of about 0.008 to about 5 mg, for example about 0.03 mg to about 5 mg, of ponesimod per kg of body weight per 1 to 2 days.

[0112] In another even more preferred embodiment there is provided a combination for use in the treatment of a patient suffering from Alzheimer's dementia comprising: (i) an S1PR modulator, and (ii) containing other therapeutic substances suitable for the treatment of Alzheimer's disease; wherein the sphingosine-1-phosphate receptor (S1PR) modulator is fingolimod (FTY720), ozanimod (RPC1063), siponimod (BAF312), or ponesimod (ACT128800), and the other therapeutic agent suitable for treating Alzheimer's dementia is selected from the group consisting of fluoxetine, citalopram, AICAR, sodium selenite, LiCl, lecanemab, and gantenerumab, the Alzheimer's dementia is familial Alzheimer's dementia, and the patient is about 40 years of age or older.

[0113] In the above embodiment, Fingolimod is administered in an amount of about 0.008 to about 5 mg, e.g., about 0.03 mg to about 5 mg, of fingolimod per kg of body weight per 1 to 2 days; Ozanimod is particularly administered in an amount of about 0.008 to about 5 mg, e.g., about 0.03 mg to about 5 mg, of ozanimod per kg of body weight per 1 to 2 days; Siponimod is particularly administered in an amount of about 0.008 to about 5 mg, e.g., about 0.03 mg to about 5 mg, of siponimod per kg of body weight per 1 to 2 days, or Ponesimod is particularly administered in an amount of about 0.008 to about 5 mg, for example about 0.03 mg to about 5 mg, of ponesimod per kg of body weight per 1 to 2 days.

[0114] For other preferred embodiments, please refer to the first aspect of the invention.

[0115] The second aspect of the invention may alternatively be formulated as follows: Use of the following combination for the manufacture of a medicament for the treatment of a patient suffering from Alzheimer's dementia: (i) an S1PR modulator, and (ii) Other therapeutic substances.

[0116] Furthermore, the second aspect of the present invention may alternatively be formulated as follows: A method for treating Alzheimer's dementia, comprising: (i) providing an S1PR modulator or a combination comprising an S1PR modulator and another therapeutic agent; (ii) administering to a patient suffering from Alzheimer's dementia a therapeutically effective amount of an S1PR modulator or a combination comprising an S1PR modulator and another therapeutic substance.

[0117] In a third aspect, the present invention relates to a pharmaceutical composition comprising a sphingosine-1-phosphate receptor (S1PR) modulator as defined in the first aspect or a combination as defined in the second aspect for use in the treatment of a patient suffering from dementia of the Alzheimer's type. Preferably, the pharmaceutical composition comprises one or more pharma- ceutically acceptable excipients, diluents, and / or carriers.

[0118] In a fourth aspect, the present invention relates to a method for treating Alzheimer's dementia comprising the steps of: (i) providing an S1PR modulator or a combination comprising an S1PR modulator and another therapeutic agent; (ii) administering to a patient suffering from Alzheimer's dementia a therapeutically effective amount of an S1PR modulator or a combination comprising an S1PR modulator and another therapeutic agent.

[0119] For preferred embodiments, please refer to the first or second aspects of the invention.

[0120] Various modifications and variations of the present invention will be apparent to those skilled in the art without departing from the scope of the present invention. Although the present invention has been described in connection with specific preferred embodiments, it should be understood that the invention as claimed should not be unduly limited to such specific embodiments. Indeed, various modifications of the described modes for carrying out the invention that are obvious to those skilled in the relevant fields are intended to be covered by the present invention. [Brief description of the drawings]

[0121] The following figures are merely illustrative of the invention and should not be construed in any way as limiting the scope of the invention as set forth in the appended claims.

[0122] [Figure 1] Photomicrograph showing that fingolimod (FTY720) reversed spine loss in CA1 pyramidal neurons in a 15-month-old male AD model mouse (Radde et al., 2006). [Diagram 2] The corresponding quantitative results of dendritic spine density analysis are shown. [Diagram 3] Fingolimod (FTY720) reversed the deficits in contextual fear learning in 15-month-old male AD mice (Radde et al., 2006). Dose: FTY720: 3.0 mg / kg / day 2 for 1 month. [Figure 4] We show that fingolimod (FTY720) reversed spine loss in CA3 pyramidal neurons and dentate granule cells in 15-month-old male AD mice ( Radde et al., 2006 ). Dose FTY720: 1.0 mg / kg / day 2 for 1 month. [Diagram 5] We show that fingolimod (FTY720) reversed spine loss in CA3 pyramidal neurons and dentate granule cells in 15-month-old male AD mice ( Radde et al., 2006 ). Dose FTY720: 3.0 mg / kg / day 2 for 1 month. [Figure 6] We show that low-dose fingolimod (FTY720) reversed spine defects in CA1 pyramidal neurons in 6-7 month-old male AD mice ( Radde et al., 2006 ). Low-dose FTY720: 0.2 mg / kg / day 2 for 1 month. [Figure 7] Chronic (4 weeks) ozanimod treatment reversed spine loss in CA1 pyramidal neurons in aged (16 months old) male AD mice ( Radde et al., 2006 ). Ozanimod dose: 1 mg / kg in drinking water for 1 month. [Figure 8]Fingolimod (FTY720) reduces the increased frequency of CD11c+ / CD14+ age-related / AD-associated microglia in the cortex of 15-month-old male AD mice.WT: wild-type littermate APP / PS1: AD mice (Radde et al, 2006)Substance A: controlSubstance B: FTY720 (1.0 mg / kg / day) for 1 month. [Figure 9] Fingolimod (FTY720) reduces the increased numbers of CD11c+ / CD14+ age-related / AD-associated microglia in the cortex of 15-month-old male AD mice.WT: wild-type littermate APP / PS1: AD mice (Radde et al, 2006)Substance A: controlSubstance B: FTY720 (1.0 mg / kg / day) for 1 month. EXAMPLES

[0123] The following examples are provided for illustrative purposes only and are not intended to limit the above invention in any way.

[0124] As an example of an S1PR modulator used to treat Alzheimer's disease, the therapeutic effect of fingolimod (FTY720) was tested in an established double transgenic amyloid precursor protein / presenilin 1 (APP / PS1) Alzheimer's disease (AD) mouse model that starts to develop amyloid-β (Aβ) pathology in the cerebral neocortex and hippocampus at 2 and 4 months of age, respectively. This AD mouse model is particularly close to human AD pathology. In these mice, LTP (long-term potentiation) impairment of Schaffer collateral CA1 synapses in ex vivo acute slices is observed at 5 months of age and becomes detectable in in vivo recordings beyond 6 months of age. Moreover, in this APP / PS1 mouse model, hippocampal-dependent learning deficits become evident at 5–8 months of age.

[0125] To test whether the AD phenotype could be ameliorated at a later stage in the APP / PS1 mouse model, fingolimod (FTY720) treatment was initiated at 15 months of age, a time when significant synaptic and memory loss had already occurred.

[0126] Male APP / PS1 mice and littermate controls (wild-type healthy mice) were treated with fingolimod (FTY720, dissolved in 3% DMSO, 1.0 mg / kg or 3.0 mg / kg body weight) by intraperitoneal (i.p.) injection every other day for 1–2 months.

[0127] Animal analyses included dendritic spine density analysis, LTP recordings, Morris water maze spatial learning and memory tests, contextual fear conditioning training and memory tests, immunohistological staining for microgliosis and astrogliosis, biochemical brain-derived neurotrophic factor (BDNF) quantification and downstream TrkB receptor (high affinity BDNF receptor) signaling, and statistical analysis.

[0128] Spine density was determined by Golgi-Cox staining of hippocampal cornu ammonia-1 (CA1) pyramidal neurons. In APP / PS1 mice, amyloid-β (Aβ) plaques were visualized with the blue fluorescent dye methoxy X-04.

[0129] Figure 1 shows secondary apical dendrites of CA1 pyramidal neurons from 15-month-old mice in vehicle- and fingolimod-treated wild-type (WT) animals (WT, top panels), APP / PS1 animals >50 μm away from the nearest plaque (AD-distal, middle panels), or APP / PS1 mice <50 μm away from the nearest plaque (AD-proximal, bottom panels). Scale bar: 5 μm for all images.

[0130] Figure 2 shows the quantification of spine density in secondary apical CA1 dendrites shown for the six different groups in Figure 1. Each bar represents the mean value of 10 dendrites of 10 different CA1 pyramidal neurons per animal (three animals per group). Horizontal bars with asterisks indicate statistical significance between selected groups. The significance of differences was tested by two-way ANOVA followed by Tukey's post-hoc test (n=30 dendrites from three animals per group). The significance level was set at 0.05 (p<0.05). Different significance levels are indicated with asterisks, **=p<0.01, ***=p<0.001.

[0131] The same effect of spine rescue in APP / PS1 mice was also observed when a much lower dose of fingolimod (FTY720), e.g., 0.2 mg / kg body weight, was applied in the same treatment regimen (see FIG. 6).

[0132] The figures show a complete rescue of spine loss in dendrites distant from plaques in fingolimod-treated APP / PS1 mice, and a significant amelioration of spine loss in dendrites close to plaques (see Figures 1 and 2; 6–7 month old AD mice). In dentate granule cells and CA3 pyramidal neurons of 15–16 month old AD mice, 1 month of FTY treatment completely rescued the spine loss near and far from Aβ plaques (see Figure 4). The number of synaptic spines could be restored to the level of age-matched healthy mice (wild-type littermates) at both ages (6–7 months and 15–16 months), indicating that short-term fingolimod (FTY720) treatment rescues Alzheimer's disease symptoms, even when massive synapse and memory loss has already occurred (see Figures 1, 2, 4, 5, 6). Fingolimod significantly reduced CD11c expression in the cortex of 15 month old male AD mice. + / CD14 + Reduces age / AD-associated increased frequency and number of microglia (see Figures 8 and 9).

[0133] Figure 3 shows that fingolimod (FTY720) reversed the deficits of contextual fear learning in 15-month-old male AD mice. Dose FTY720: 3.0 mg / kg / day 2 for 1 month.

[0134] Figure 7 shows that another S1PR modulator (ozanimod) has a very similar ability to restore spine loss in CA1 pyramidal neurons in aged (16 month old) male AD mice. Ozanimod dose: 1 mg / kg in drinking water for 1 month, starting at month 15.

[0135] Figure 4 shows that fingolimod (FTY720) reversed spine loss in CA3 and dentate gyrus pyramidal neurons in 15-month-old male AD mice. Dose FTY720: 1.0 mg / kg / day 2 for 1 month.

[0136] Figure 5 shows that fingolimod (FTY720) reversed spine loss in CA3 and dentate gyrus pyramidal neurons in 15-month-old male AD mice. Dose FTY720: 3.0 mg / kg / day 2 for 1 month.

[0137] Figure 6 shows that low-dose fingolimod (FTY720) reversed spine defects in CA1 pyramidal neurons in 6-7 month-old male AD mice. Low-dose FTY720: 0.2 mg / kg / day 2 for 1 month.

[0138] Figure 8 shows that fingolimod (FTY720) suppressed CD11c expression in the cortex of 15-month-old male AD mice. + / CD14 + It is shown that it reduces the increase in the frequency of aging / AD-related microglia. WT: wild-type littermates, APP / PS1: AD mice (Radde et al., 2007) Substance A: control, substance B: FTY720 (1.0 mg / kg / day 2) for one month.

[0139] Figure 9 shows that fingolimod (FTY720) suppressed CD11c expression in the cortex of 15-month-old male AD mice. + / CD14 + This shows that FTY720 reduces the increase in microglia associated with aging / AD. WT: wild-type littermates, APP / PS1: AD mice (Radde et al., 2007), Substance A: control, Substance B: FTY720 (1.0 mg / kg / day 2) for 1 month.

[0140] While certain representative embodiments and details have been shown to illustrate the invention, it will be apparent to those skilled in the art that various changes and modifications are possible and that, within the scope of the appended claims, the invention may be practiced other than as specifically described and claimed.

[0141] References Radde R, Bolmont T, Kaeser SA, Coomaraswamy J, Lindau D, Stoltze L, Calhoun ME, Jaggi F, Wolburg H, Gengler S, Haass C, Ghetti B, Czech C, Holscher C, Mathews PM, Jucker M. Abeta42-driven cerebral amyloidosis in transgenic mice reveals early and robust pathology. EMBO Rep. 2006 Sep;7(9):940-6. doi:10.1038 / sj.embor.7400784. Epub 2006 Aug 11. PMID:16906128; PMCID:PMC1559665.

Claims

1. A sphingosine-1-phosphate receptor (S1PR) modulator for use in the treatment of a patient suffering from Alzheimer's dementia, wherein said S1PR modulator is ozanimod (RPC1063).

2. 2. The S1PR modulator for use according to claim 1, wherein the patient suffering from Alzheimer's dementia is about 40 years of age or older.

3. The S1PR modulator for use according to claim 1, wherein the Alzheimer's dementia is sporadic Alzheimer's dementia or familial Alzheimer's dementia.

4. 2. The S1PR modulator for use according to claim 1, wherein the treatment is effective in ameliorating Alzheimer's dementia.

5. 2. The S1PR modulator for use according to claim 1, wherein the S1PR modulator is administered intraperitoneally or orally.

6. An S1PR modulator for use as described in claim 1, wherein ozanimod is administered in an amount of 0.008 mg to 5 mg of S1PR modulator per kg of body weight per 1 to 2 days.

7. An S1PR modulator for use as described in claim 6, wherein ozanimod is administered in an amount of 0.008 mg to 3 mg of ozanimod per kg of body weight per two days.

8. 7. The S1PR modulator for use according to claim 6, wherein the administration is carried out over a period of about 1 month to 24 months, preferably over a period of about 1 month to 12 months, such as about 1 month to 6 months, or about 1 month to 2 months.

9. 2. The S1PR modulator for use according to claim 1, wherein the patient to be administered is a patient who has undergone / is undergoing behavioral therapy, reality orientation training, physical therapy, occupational therapy, or cognitive training (memory training), or a combination thereof.

10. 2. The S1PR modulator for use according to claim 1, wherein the S1PR modulator is used in combination with an agent selected from the group consisting of aducanumab, lecanemab, gantenerumab, riluzole, donepezil, fluoxetine, citalopram, methylene blue, curcumin, lithium chloride, roscovitine, memantine, sodium selenate, pyridoxamine (vitamin B6), and 5-aminoimidazole-4-carboxamide-1-β-D-ribofuranoside (AICAR).

11. 1. A combination for use in treating a patient suffering from Alzheimer's dementia, said combination comprising: (i) an S1PR modulator, and (ii) contains other therapeutic substances; The combination wherein said S1PR modulator is ozanimod (RPC1063).

12. 12. The combination for use of claim 11, wherein the other therapeutic agent is selected from the group consisting of aducanumab, lecanemab, gantenerumab, riluzole, donepezil, fluoxetine, citalopram, methylene blue, curcumin, lithium chloride, roscovitine, memantine, sodium selenate, pyridoxamine (vitamin B6), and 5-aminoimidazole-4-carboxamide-1-β-D-ribofuranoside (AICAR).

13. 12. A pharmaceutical composition comprising a sphingosine-1-phosphate receptor (S1PR) modulator as defined in claim 1 or a combination as defined in claim 11 for use in the treatment of patients suffering from dementia of the Alzheimer's type.

14. For the manufacture of a pharmaceutical product for the treatment of patients suffering from Alzheimer's disease, (i) an S1PR modulator, and (ii) the use of a combination of other therapeutic agents, The S1PR modulator is ozanimod (RPC1063).

Images