Use of a t1r3 agonist sucralose in the alleviation of alzheimer's disease and related cognitive impairments

Abstract

The application discloses application of T1R3 agonist sucralose in relieving Alzheimer's disease and related cognitive impairment, and aims at brain glucose metabolism disorder and cognitive decline problem, and the application takes sucralose as the only pharmaceutical active ingredient, corrects brain glucose metabolism disorder through targeting brain astrocyte sweet taste receptor T1R3, and then treats and relieves neurodegenerative diseases. The application is proved by animal experiments that cognitive dysfunction of AD model mice can be improved in a full range of molecular mechanisms, cell functions, tissue metabolisms and whole behavior, and a variety of dosage forms and medication strategies can be selected, and the application has good in-vivo safety and clinical transformation potential.

Description

Technical Field

[0001] This invention relates to the application of sucralose, and more particularly to the application of sucralose as a T1R3 agonist in alleviating Alzheimer's disease and related cognitive impairment. Background Technology

[0002] Alzheimer's disease (AD) is the most common neurodegenerative disease, characterized by decreased brain glucose metabolism (a hypometabolic pattern visible on FDG-PET) in the preclinical / early stages and closely related to cognitive impairment. Therefore, "restoring brain energy metabolism and glucose utilization" has long been considered a potential intervention direction, but effective and safe drugs specifically improving brain energy metabolism are lacking. Mechanistically, abnormalities in the blood-brain barrier and microvascular / glial-neuronal metabolic coupling are associated with the development and progression of AD, and decreased Glut1 levels can exacerbate cerebrovascular-neuronal dysfunction, Aβ pathology, behavioral deficits, and neurodegeneration. Research on AD and the above mechanisms includes:

[0003] 1. Activating astrocyte glucose metabolism / enhancing Glut1 expression: Some technologies propose using specific plant hydrophobic extracts to activate astrocyte glucose metabolism, improve neurological function, and can be used for dementia / AD-related brain function decline, emphasizing "activation of astrocyte glucose metabolism" and improvement of Glut1 / MCT expression;

[0004] 2. Basic and pharmacological aspects of the T1R3 / TAS1R family of sweet taste receptors: Sweet taste receptors are composed of T1R2 / T1R3 and can recognize a variety of sweet molecules, including sucrose and saccharin; related basic research provides a receptor biological basis for "pharmacological intervention targeting T1R3";

[0005] 3. Dementia-related formula patents that use "sucralose" as a flavoring / excipient for drugs: For example, CN103349198A is a collagen powder for preventing Alzheimer's disease. Its formula contains sucralose, but its function is only to improve the taste, while the overall activity is attributed to the combination of complex nutrients.

[0006] 4. T1R3 and cellular metabolism / autophagy signaling pathways: Previous studies have shown that T1R1 / T1R3 can affect the localization / activity of mTORC1 and regulate autophagy, suggesting that the "taste receptor-autophagy-metabolic transporter" can theoretically constitute a pharmacological link; however, its specific role and therapeutic potential in AD astrocytes and brain glucose metabolism are still emerging directions.

[0007] In summary, there are currently no effective and well-defined treatment strategies for Alzheimer's disease and related cognitive impairments, especially the brain glucose metabolism disorders and cognitive decline that occur in the early stages of AD. Summary of the Invention

[0008] Purpose of the invention: The purpose of this invention is to provide the application of sucralose in alleviating Alzheimer's disease and related cognitive impairment, and to provide multiple routes of administration, including oral administration, and their mechanisms of action.

[0009] Technical solution: This invention provides the application of sucralose as an active ingredient in the preparation of drugs for treating neurodegenerative diseases.

[0010] The inventors discovered that the astrocyte sweet taste receptor T1R3 is a key upstream molecule regulating Glut1 expression. By correcting the decreased expression / localization of Glut1 at the astrocyte glucose transporter and inhibiting abnormal autophagy activation, it can improve brain glucose metabolism and alleviate cognitive impairment. Furthermore, this study is the first to demonstrate that sucralose specifically activates T1R3 in astrocytes, improving cognitive function in AD model animals. This discovery provides new ideas, targets, and drugs for the treatment of neurodegenerative diseases, including AD.

[0011] Technical Principle: Sucralose, as a non-metabolizable high-affinity T1R3 agonist, is not broken down into glucose by the body and does not increase peripheral blood glucose levels. After oral absorption, it crosses the blood-brain barrier and specifically acts on the T1R3 receptors on the surface of astrocytes in the hippocampus, activating downstream cell signaling pathways. It effectively inhibits the abnormally elevated autophagy pathway activation in AD pathology, blocks the degradation and intracellular retention of Glut1 protein due to excessive autophagy, thereby restoring the total protein expression level, cell membrane localization ratio, and glucose transport function of Glut1. It enhances glucose uptake, utilization, and energy metabolism in key cognitive brain regions such as the hippocampus, repairs the expression of synapse-associated protein PSD-95 and the structure and function of neural synapses, and ultimately improves short-term and long-term working memory and spatial learning ability in patients with neurodegenerative diseases, achieving comprehensive improvement from molecular mechanisms, cellular function, tissue metabolism to overall behavior.

[0012] The neurodegenerative diseases mentioned include Alzheimer's disease and related cognitive impairments.

[0013] The preferred dosage forms of the drug are oral solutions / suspensions, tablets / capsules, orally disintegrating tablets / oral films, sustained-release formulations, and nanodelivery systems. Sucralose, as the core active ingredient of this invention, can be prepared into various dosage forms according to clinical application scenarios, patient needs, and targeted delivery objectives. The core purpose is to effectively increase the exposure of sucralose in the brain, achieving precise targeting of neurovascular units, thereby fully realizing its medicinal efficacy.

[0014] Oral solutions / suspensions offer advantages such as convenient administration and rapid absorption, making them particularly suitable for elderly patients with swallowing difficulties and bedridden patients. By optimizing the solubilizers, suspending agents, and pH adjusters in the formulation, the solubility and stability of sucralose in water can be addressed, ensuring uniform concentration and stable efficacy during storage. At the same time, it accelerates the gastrointestinal absorption rate and shortens the time to peak concentration, laying the foundation for targeted delivery to the brain.

[0015] Tablets / capsules are the most commonly used solid dosage forms in clinical practice. During the preparation process, by selecting appropriate fillers, disintegrants, binders and lubricants, and optimizing the tableting or filling process, the disintegration rate of tablets and the dissolution rate of capsules can meet the pharmacopoeia requirements, ensuring that sucralose is rapidly released and absorbed in the gastrointestinal tract, and then transported to the brain through blood circulation to increase the drug concentration in the brain.

[0016] Orally disintegrating tablets / oral films are designed for specific drug administration scenarios. Orally disintegrating tablets can disintegrate rapidly in the mouth without the need for water, further improving the convenience of drug administration. Oral films can be directly absorbed through the oral mucosa, avoiding the first-pass effect of the liver, reducing drug degradation in the gastrointestinal tract, significantly improving bioavailability, and shortening the onset time of drug action. They are more suitable for scenarios that require rapid drug efficacy, especially for patients with impaired consciousness or those who cannot swallow normally.

[0017] Sustained-release formulations encapsulate sucralose with sustained-release materials (such as polylactic acid and hydroxypropyl methylcellulose) to achieve slow and continuous drug release. This can effectively prolong the duration of drug action in the body, maintain stable drug concentration in the brain, and reduce adverse reactions that may occur due to excessively high blood drug concentrations. They are especially suitable for the treatment of chronic diseases that require long-term medication.

[0018] Nanoparticle delivery systems (mainly including liposomes and polymer nanoparticles) are key dosage forms for achieving targeted delivery to the brain. Their particle size is typically controlled between 10-100 nm, allowing them to penetrate the blood-brain barrier and enter brain tissue via the endothelial cell gaps and active transport mechanisms, precisely targeting neurovascular units. Liposomes offer advantages such as good biocompatibility, strong sustained-release properties, and high modifiability; surface modification with targeting ligands (such as transferrin and lactoferrin) can further enhance their targeting of neurovascular units. Polymer nanoparticles, on the other hand, feature high drug loading capacity, good stability, and mature preparation processes. They can effectively protect sucralose from enzymatic degradation in vivo, increasing drug accumulation in the brain and enhancing efficacy.

[0019] In existing technologies, sucralose is typically used as an excipient or solubilizer, with its core function being to assist the main drug in exerting its efficacy. However, the core innovation of this invention lies in positioning sucralose itself as an active ingredient. Through the design and optimization of various dosage forms, its medicinal value is fully explored, enabling targeted treatment of brain diseases. This breaks through the limitations of sucralose application in existing technologies and forms a completely new technical path.

[0020] Preferably, sucralose is used as a standalone treatment or in combination with other treatments for Alzheimer's disease.

[0021] At the monotherapy level, sucralose can be used clinically as a standalone treatment for target indications (such as related neurodegenerative diseases). Its core advantages as a monotherapy lie in its simple dosing regimen and controllable adverse reactions. Through standardized dose gradient studies, the optimal dosage, frequency, and duration of treatment can be determined for different populations (e.g., patients of different ages, disease durations, and those with underlying diseases), providing clear treatment evidence for monotherapy scenarios in clinical practice. Simultaneously, it can provide basic data support for the design of subsequent combination therapy regimens, ensuring dosage safety and synergistic efficacy when using combination therapy.

[0022] At the level of combination therapy development strategies, sucralose can be used in combination with currently clinically approved standard treatments or disease-modifying therapies. Key areas for combination include cholinesterase inhibitors, memantine, and anti-Aβ antibodies. Cholinesterase inhibitors (such as donepezil and rivastigmine) primarily improve cognitive function by inhibiting cholinesterase activity and increasing acetylcholine levels in the brain. Memantine, as a non-competitive NMDA receptor antagonist, can regulate glutamatergic neurotransmission in the brain, slowing disease progression. Anti-Aβ antibodies reduce neurotoxicity by specifically binding to Aβ protein and decreasing its deposition. All three are mainstream treatments for Alzheimer's disease. This type of combination therapy strategy is not a random combination, but strictly follows the requirements of relevant clinical research and development guidelines. The guidelines explicitly encourage the exploration of the combined use of drugs with different mechanisms of action for the target indication, so as to achieve the treatment goals of improved efficacy, reduced adverse reactions, and delayed disease progression through complementary mechanisms. At the same time, for some indications where the efficacy of monotherapy is limited and the disease progresses rapidly, combination therapy is also a core dimension that needs to be considered in clinical research and development. It can effectively fill the clinical gaps of monotherapy and meet specific clinical needs.

[0023] In subsequent clinical research and development, for combination therapy strategies, it is necessary to focus on the safety and efficacy studies of combination therapy, clarify the synergistic mechanism of sucralose with various combination drugs, the optimal combination dose ratio, the dosing sequence, and the occurrence of adverse reactions of combination therapy. At the same time, in accordance with the requirements of the guidelines, the clinical trial design of combination therapy should be improved to ensure the scientificity, rationality and clinical feasibility of combination therapy regimens, so as to provide more comprehensive support for the clinical promotion and application of sucralose.

[0024] Beneficial effects: Compared with the prior art, the present invention has the following significant advantages:

[0025] 1. Efficacy: Animal model empirical evidence supports that sucralose, as a T1R3 agonist, can improve brain glucose metabolism and alleviate cognitive impairment, achieving comprehensive improvement from molecular mechanisms, cell function, tissue metabolism to overall behavior.

[0026] 2. Higher alignment with disease mechanisms: Correcting brain energy metabolism using astrocytes and Glut1 as key nodes echoes the evidence chain of early AD pathology of "hypometabolism" and Glut1 deficiency. At the molecular / cellular level: Restoring Glut1-related indicators (total expression, membrane / intracellular ratio, localization and distribution) and mechanistically linking it to pathways such as autophagy / mTORC1; while knockdown of hippocampal T1R3 significantly weakens / eliminates the above benefits, suggesting a "target-effect" relationship.

[0027] 3. Different dosage forms, as well as single-drug or combination therapy strategies, can be selected according to clinical needs.

[0028] 4. Safety: Sucralose is commonly used as a food additive and has good tolerability and convertibility within a reasonable dosage range.

[0029] 5. Less metabolic burden on the system: Unlike "sugar-added / glucose-raising intervention", comparative studies show that oral sucrose has no significant effect on improving the perception of 5×FAD and can increase fasting blood glucose, suggesting that sucralose, as a "non-glucose-to-glucose" T1R3 agonist, has a greater advantage in terms of systemic metabolic burden.

[0030] 6. Expandable clinical companion diagnostics / pharmacodynamic evaluation system: FDG-PET or other metabolic imaging can be used to directly quantify improvements in brain glucose metabolism in clinical practice, forming a closed loop of "mechanism-biomarker-clinical benefit" and improving the success rate of translation. Attached Figure Description

[0031] Figure 1 Pathological tissue diagram of downregulated T1R3 expression in astrocytes from AD patients and a 5×FAD mouse model;

[0032] Figure 2The expression level of Glut1 in T1R3 astrocytes is regulated by autophagy.

[0033] Figure 3 The combined use of sucralose and glutamate was used to improve the decrease in T1R3 and Glut1 expression levels in primary cultured astrocytes caused by Aβ treatment.

[0034] Figure 4 Behavioral tests confirmed that sucralose treatment can improve cognitive dysfunction and enhance spatial learning and memory abilities in AD model mice.

[0035] Figure 5 Sucralose treatment can improve Glut1 expression levels and synaptic-related indicators in AD model mice. Detailed Implementation

[0036] The technical solution of the present invention will be further described below with reference to the accompanying drawings.

[0037] Example 1

[0038] This embodiment provides a pharmaceutical application solution that uses sucralose as the sole pharmaceutically active ingredient, and corrects brain glucose metabolism disorders by targeting the T1R3 sweet taste receptor in astrocytes, thereby treating and alleviating AD and related cognitive impairment.

[0039] Experimental Design: A standardized animal experimental method was adopted, which involved oral administration of 0.78 mM sucralose for 4 weeks. 5×FAD transgenic AD model mice were used as experimental subjects, and wild-type C57BL / 6 mice were used as normal controls. The subjects were randomly assigned to blank control group, model control group, sucralose intervention group, T1R3 knockdown control group, and T1R3 knockdown + sucralose intervention group. Irrelevant variables such as age, sex, and breeding environment were excluded, and the entire research process was carried out in strict accordance with animal experimental ethics.

[0040] Experimental Methods: Using publicly available databases, human tissue samples, and wild-type C57BL / 6 and 5×FAD transgenic AD model mice, the expression of T1R3 in hippocampal astrocytes under AD background was confirmed by immunofluorescence staining. Five-month-old 5×FAD transgenic AD model mice were randomly divided into an AD model group, a sucralose intervention group, an AD model hippocampal T1R3 knockdown group, and an AD model hippocampal T1R3 knockdown sucralose intervention group. Mice in the sucralose intervention group received free access to 0.78 mM sucralose solution for 4 consecutive weeks, while the other groups received the same amount of sterile water, with all other feeding conditions remaining consistent. After the administration period, behavioral tests such as the Y-maze and Barnes' maze were performed to assess short-term and long-term working memory and spatial learning abilities. After the behavioral tests, tissue samples were collected from the mice, and hippocampal tissue was rapidly separated and analyzed using Western spectroscopy. Using blot and immunofluorescence staining techniques, the expression levels of T1R3, Glut1, and PSD-95 proteins in hippocampal tissue were detected, as well as the co-localization of Glut1 with the astrocyte marker GFAP. Simultaneously, autophagy pathway-related proteins were detected to verify the target and molecular mechanism of sucralose. Furthermore, by constructing an astrocyte T1R3-specific knockdown cell model, and setting up a knockdown control group and a sucralose intervention group after knockdown, the study reversely verified that T1R3 is an essential target for sucralose to exert its therapeutic effect.

[0041] Experimental results are as follows Figure 1-5 As shown.

[0042] Figure 1 This study shows downregulated T1R3 expression in astrocytes of AD patients and a 5×FAD mouse model. A is a volcano plot showing T1R3 expression in IPSC-induced astrocytes from AD patients in a publicly available database (GSE243177). B is a representative immunofluorescence image showing T1R3 expression levels in astrocytes from hippocampal samples of healthy humans and AD patients (scale bar: 50 μm) (n = 3 per group). CD are representative immunofluorescence images and bar graphs showing T1R3 expression levels in the hippocampus of 4-5 month old male WT and 5×FAD groups (scale bar: 100 μm) (n = 6 per group). E is a representative Western blot image and bar graph showing APP and T1R3 expression levels in 4-5 month old male WT and 5×FAD groups (n = 6 per group). Results are expressed as mean ± standard error and analyzed using a t-test.

[0043] Figure 2The decrease in T1R3 was shown to lead to a reduction in Glut1 by enhancing autophagy activity in astrocytes. A shows a GSEA analysis of the GSE243177 database, demonstrating significant enrichment of differentially expressed genes in the lysosomal and phagosome pathways between IPSC-induced astrocytes from AD patients and controls. B shows representative Western blotting images and statistical plots, indicating the protein levels of LC3-II in primary cultured astrocytes treated with DMSO and chloroquine (CQ) (40 μM) within 4 hours prior to collection (n = 3 per group). C shows representative Western blotting images and bar graphs, indicating the expression levels of T1R3 and Sqstm1 in primary cultured astrocytes after T1R3 knockdown via siRNA (n = 3 per group). D shows representative immunofluorescence images, indicating the GFP / RFP signal ratio (scale bar: 20 μm) in primary cultured control astrocytes and astrocytes after T1R3 knockdown via siRNA (n = 10 per group). E shows representative immunofluorescence images, displaying the intensity of LAMP1 in different groups; the right side shows a bar chart with overlaid dot plots, displaying the corresponding quantitative immunofluorescence intensity (scale bar: 10 μm) (n = 20 per group). F shows representative Western blotting images and statistical graphs, displaying the Glut1 protein level in primary cultured astrocytes treated with DMSO and bafilomycin A1 (Baf A1) (50 μM) within 24 hours prior to collection (n = 3 per group). Results are expressed as mean ± standard error. C, D, and E were analyzed using t-tests, while B and F were analyzed using two-way ANOVA and post-hoc pairwise comparisons.

[0044] Figure 3 This study showed that the combination of the sweetener sucralose and glutamate improved the decrease in TIR3 and Glut1 expression levels in primary cultured astrocytes induced by Aβ treatment. A represents the chemical structure of sucralose. B shows representative Western blot images of TIR3 and Glut1 protein levels in the control group and the Aβ (10 μM, 72 h) treatment group. The experimental groups were treated with or without glutamate (5 mM, 72 h) and sucralose (0.1 mM, 72 h), respectively (n = 3 per group). Results are expressed as mean ± standard error and were analyzed using two-way ANOVA and post-hoc pairwise comparisons.

[0045] Figure 4This study demonstrates that treatment with the sweetener sucralose can improve cognitive dysfunction and enhance spatial learning and memory in 5×FAD model mice. A is the experimental flowchart, showing that 5-month-old male WT and 5×FAD mice were administered sucralose (0.78 mM) orally via water for 4 weeks, followed by behavioral testing and histopathological observation. B is a trajectory diagram showing representative movement trajectories in the Y maze for 6-month-old male 5×FAD mice, 5×FAD mice administered sucralose orally, 5×FAD mice with T1R3 knockdown in the hippocampus, and 5×FAD mice with T1R3 knockdown in the hippocampus and administered sucralose orally. The right side shows a bar chart with overlaid dots, displaying the percentage of time mice spent in the new arms of the maze and the number of times they entered the new arms (n=10 mice per group). C is a trajectory plot showing representative movement trajectories of 6-month-old male 5×FAD mice, 5×FAD mice orally administered sucralose mice, 5×FAD mice with T1R3 knockdown in the hippocampus, and 5×FAD mice with T1R3 knockdown in the hippocampus and orally administered sucralose in the NOR test; the right side is a bar chart of the overlay plot showing the percentage of time spent exploring new objects (n=10 mice per group). D's upper plot is a trajectory plot showing representative movement trajectories of 6-month-old male 5×FAD mice, 5×FAD mice orally administered sucralose mice, 5×FAD mice with T1R3 knockdown in the hippocampus, and 5×FAD mice with T1R3 knockdown in the hippocampus and orally administered sucralose in the Barnes maze exploration phase; the lower left plot is a line graph showing the latency of the learning training phase; the lower right plot is a bar chart of the overlay plot showing the latency of the exploration phase (n=10 mice per group). Results are expressed as mean ± standard error, and analysis was performed using two-way ANOVA and post-hoc pairwise comparisons.

[0046] Figure 5This study demonstrates that treatment with the sweetener sucralose improves Glut1 expression levels and synaptic-related indices in 5×FAD model mice. Image A shows representative immunofluorescence images of Glut1 and GFAP expression in 6-month-old male 5×FAD mice, mice treated with sucralose, mice with T1R3 knockdown in the hippocampus, and mice with T1R3 knockdown in the hippocampus treated with sucralose (scale bar: 20 μm) (n = 5 per group). Image B shows representative Western blot images and bar charts of superimposed dot plots of Glut1 expression in 6-month-old male 5×FAD mice and mice treated with sucralose (n = 4 per group). C represents the bar charts of representative protein blots and overlay plots of PSD-95 expression in 6-month-old male 5×FAD mice, 5×FAD mice orally administered sucralose, 5×FAD mice with T1R3 knockdown in the hippocampus, and 5×FAD mice with T1R3 knockdown in the hippocampus orally administered sucralose (n = 5 for each group). Results are expressed as mean ± standard error. A and C were analyzed using two-way ANOVA and post-hoc pairwise comparisons, while B was analyzed using a t-test.

[0047] The research findings are summarized below.

[0048] At the molecular and cellular levels, intervention with 0.78 mM sucralose for 4 weeks significantly upregulated the protein expression levels of T1R3 and Glut1 in the hippocampus of 5×FAD model mice, effectively corrected the abnormal retention of Glut1 in astrocytes, increased the proportion of Glut1 localized on the cell membrane, enhanced glucose transport function, reduced the degradation of Glut1 by autophagosomes, and significantly restored the expression of postsynaptic dense protein PSD-95, repairing the damaged neural synaptic structure and function under AD pathological conditions.

[0049] At the tissue metabolism level, this administration regimen can effectively increase glucose uptake and metabolism rate in the hippocampus of model mice, improve the characteristic low glucose metabolism state of AD, repair the metabolic coupling function of cerebral blood vessels-glial cells-neurons, and provide sufficient energy supply for nerve cells.

[0050] At the overall behavioral level, after 4 weeks of oral intervention with 0.78 mM sucralose, 5×FAD model mice showed a significant increase in new arm dwell time and number of entries in the Y maze experiment, and a significant improvement in short-term working memory. In the Barnes maze experiment, the escape latency during the spatial learning training period was significantly shortened, and the dwell time in the target quadrant during the exploration period was significantly prolonged, indicating that spatial learning and long-term memory abilities were effectively improved.

[0051] In the hippocampal T1R3 knockdown model mice, sucralose failed to upregulate Glut1 expression, improve brain glucose metabolism and cognitive function, fully demonstrating that T1R3 is the key target for sucralose to exert its brain metabolic protection and cognitive improvement effects.

[0052] Meanwhile, compared with traditional sucrose intervention, this technical solution has the core advantages of not increasing peripheral fasting blood glucose and having no systemic metabolic burden, thus avoiding the metabolic risks brought about by carbohydrate intervention. Moreover, at this dosage concentration and cycle, sucralose has no adverse effects on mouse body weight, organ index, blood routine and biochemical indicators, demonstrating good in vivo safety and clinical translation potential. It can directly provide standardized dosing parameters and mechanism basis for subsequent oral formulation development and clinical trial design.

[0053] In summary, this embodiment addresses the core technical challenges of early-stage Alzheimer's disease, including decreased brain glucose metabolism, defects in Glut1 expression and membrane localization in hippocampal astrocytes, excessive activation of abnormal autophagy, impaired synaptic function, and cognitive impairment related to learning and memory. It employs a treatment approach using sucralose to achieve the following two objectives: First, it enhances / restores the glucose metabolic rate (CMRglc) and 18F-FDG uptake rate (SUV / SUVR) in specific brain regions. The primary target brain region in this study is the hippocampus, which is closely related to cognitive function and is a key regulatory area for learning, memory, and other cognitive functions. A decrease in glucose metabolism in this region directly leads to cognitive decline. Second, it improves the metabolic network in cognitively related brain regions, repairs abnormal metabolic connections between brain regions, promotes the balanced distribution and efficient utilization of glucose in various cognitively related brain regions, and alleviates neurological damage caused by brain metabolic disorders. Astrocytes are important neural support cells in the brain, and the glucose transport pathways they mediate (especially the Glut1-related pathway) are crucial for maintaining brain glucose homeostasis. Abnormalities in this pathway can lead to ineffective glucose transport from the bloodstream to nerve cells, resulting in cognitive impairment. One of the core mechanisms of the sucralose intervention in this protocol is to regulate the normal function of this pathway, specifically including: improving the expression level of Glut1 (glucose transporter 1) in the memory-related hippocampus, correcting the abnormal state of insufficient Glut1 expression; repairing abnormal Glut1 membrane localization, promoting Glut1 translocation to the astrocyte membrane surface, and enhancing its glucose transport capacity; ultimately achieving the technical effect of alleviating cognitive impairment.

Claims

1. The application of sucralose in the preparation of drugs for treating neurodegenerative diseases, characterized in that, Sucralose is the active ingredient.

2. The application according to claim 1, characterized in that, The neurodegenerative diseases mentioned include Alzheimer's disease and related cognitive impairments.

3. The application according to claim 1, characterized in that, The dosage forms of the drugs include oral solutions / suspensions, tablets / capsules, orally disintegrating tablets / oral films, sustained-release formulations, and nanodelivery systems.

4. The application according to claim 3, characterized in that, The oral solution / suspension also contains a solubilizer, a suspending agent, and a pH adjuster; the tablets / capsules also contain a filler, a disintegrant, a binder, and a lubricant; the sustained-release formulation uses polylactic acid or hydroxypropyl methylcellulose as the sustained-release material.

5. The application according to claim 3, characterized in that, The particle size of the nanodelivery system is 10-100 nm.

6. The application according to claim 3, characterized in that, The nanodelivery system includes liposomes and polymer nanoparticles.

7. The application according to claim 6, characterized in that, The liposomes are surface-modified with targeting ligands.

8. The application according to claim 7, characterized in that, The targeting ligand is transferrin or lactoferrin.

9. The application according to claim 1, characterized in that, Sucralose can be used as a standalone treatment or in combination with other treatments for Alzheimer's disease.

10. The application according to claim 9, characterized in that, Other therapeutic agents include cholinesterase inhibitors, memantine, and anti-Aβ antibodies.

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