CN-122005861-A - Application of KLF4 serving as target spot in APOE4 genotype Alzheimer disease

Abstract

The invention relates to an application of KLF4 serving as a target spot in APOE4 genotype Alzheimer disease, belonging to the technical field of biological medicine. The invention provides application of KLF4 in preparation of any one of (1) improving learning and memory ability injury, (2) improving blood brain barrier function and (3) treating or preventing neurodegenerative diseases. The present invention found that KLF4 was significantly reduced in both APOE4 genotype patients and in the cerebral cortex of mice, APOE4 mice had significantly lower KLF4 than APOE3 mice, and APOE4 carrier cortex was expressed less than non-carrier. The invention takes the APOE4 as an incision point for intensive research, and discovers that the APOE4 can lower the KLF4 expression and destroy the BBB structure, so that learning and memory damage is caused, the learning and memory damage is further developed into neurodegenerative diseases, and the symptoms can be improved by over-expressing the KLF 4.

Inventors

• QIN DAJIANG
• WEI ZIYING
• YAO YUXIAO
• LIU CHUNHUA
• Ling Yixia

Assignees

• 广州医科大学附属第五医院(广州再生医学与健康广东省实验室附属医院)

Dates

Publication Date

20260512

Application Date

20260128

Claims (10)

1. Use of klf4 in the manufacture of any one of the following medicaments: (1) Improving learning and memory impairment; (2) Improving blood brain barrier function; (3) Treating or preventing neurodegenerative diseases.
2. 2. The use of claim 1, wherein the blood brain barrier is an APOE4 mediated blood brain barrier.
3. 3. The use of claim 1, wherein the improvement in blood brain barrier function is a decrease in blood brain barrier permeability.
4. 4. The use according to claim 1, wherein the neurodegenerative disease is APOE type 4 alzheimer's disease.
5. 5. Use of an agent that overexpresses KLF4 in the preparation of any one of the following: (1) Improving learning and memory impairment; (2) Improving blood brain barrier function; (3) Treating or preventing neurodegenerative diseases.
6. 6. The use according to claim 5, wherein the agent that overexpresses KLF4 is a viral vector or a non-viral vector comprising the KLF4 gene sequence.
7. 7. The use according to claim 6, wherein the viral vector is any one of a lentiviral vector, an adenoviral vector, an adeno-associated viral vector, a retroviral vector.
8. 8. The use according to claim 6, wherein the non-viral vector is any one of a plasmid vector, a liposome, a nanocarrier.
9. 9. A pharmaceutical composition for improving impaired learning and memory comprising an agent that overexpresses KLF 4.
10. 10. The pharmaceutical composition of claim 9, further comprising a pharmaceutically acceptable adjuvant.

Description

Application of KLF4 serving as target spot in APOE4 genotype Alzheimer disease Technical Field The invention relates to the technical field of biological medicine, in particular to an application of KLF4 serving as a target point in APOE4 genotype Alzheimer disease. Background Alzheimer's Disease (AD) is a highly neurodegenerative Disease. Among the multiple causative factors of AD, the genetic factor plays a decisive role, wherein the APOE gene is the strongest genetic risk factor which is well-defined, three main subtypes epsilon 2, epsilon 3 and epsilon 4 exist, the disease risk of the population carrying epsilon 4 subtype (APOE 4) is increased in a dose-dependent manner, the disease risk of the population carrying 1 APOE4 allele is increased 3-4 times compared with that of epsilon 3 homozygote, the lifetime disease risk of the population carrying 2 alleles is up to 60% -70%, and the disease age is 5-10 years earlier. The mechanism of APOE4 mediated AD pathogenesis has a multidimensional character and is deeply interleaved with other pathological pathways: The metabolism and epigenetic disorder is discovered by the group Liu Jiang of Chinese university of science and technology that glial cell-derived ApoE4 protein can inhibit key enzyme for synthesizing neuron cholesterol, cause accumulation of acetyl-CoA and abnormally regulate histone acetylation, further interfere with transcriptional regulation of learning and memory related genes, and the regulation capacity of the apoE4 protein is obviously weaker than that of a protective epsilon 2 subtype. Aβ and tau pathology exacerbation APOE4 promotes amyloid plaque deposition by decreasing Aβ clearance efficiency while enhancing tau protein aberrant phosphorylation and tangle formation and can be directly conjugated with Aβ oligomers to exacerbate neurotoxicity. The nerve inflammation amplification effect is that APOE4 can activate microglial cell TREM2-CD36 signal channel to promote the release of pro-inflammatory factors (IL-1 beta and TNF-alpha) and form malignant circulation of inflammation-nerve injury. However, the existing AD treatment technology has significant limitations on APOE4 high risk/definitive populations, becoming a technical bottleneck to be broken through urgently: 1. traditional symptomatic treatment has weak curative effect on APOE4 population and increased risk Cholinesterase inhibitors (e.g., donepezil) and NMDA receptor antagonists (e.g., memantine) only slightly improve symptoms and have poorer cognitive decline delay in APOE4 carriers-clinical data indicate that APOE4 homozygous patients have a 23% faster decline in cognitive function scores than non-carriers after donepezil administration. More seriously, APOE4 carriers often have increased cardiovascular risk, and the incidence of bradycardia, blood pressure fluctuations, etc. side effects induced by the above drugs increases by 40% in this population, limiting clinical use. 2. Disease modification treatment has a "efficacy-safety" double dilemma for APOE4 populations In recent years, the obtained Abeta targeted monoclonal antibodies (such as doramectin and rankanolamine monoclonal antibodies) can delay early AD cognitive decline, but have deadly limitation on the population of the APOE4, on one hand, when the Abeta targeted monoclonal antibodies are used by an Aboe 4 carrier, the occurrence rate of cerebral edema (ARIA-E) reaches 37 percent, 13 percent higher than that of a non-carrier, the risk of micro hemorrhage (ARIA-H) is increased to 41 percent, the Abeta targeted monoclonal antibodies are even partially excluded by clinical tests, and on the other hand, the medicine is only suitable for early patients with Abeta positive, and the speed of the Aboe 4 carrier from light cognitive disorder to dementia is faster, so that the treatment window period is often missed. In addition, the existing medicines are not designed for the specific mechanisms of APOE4 such as metabolic disorder, inflammation amplification and the like, and cannot block the core pathogenic pathways. 3. The APOE4 targeted intervention technology has a fundamental gap Although APOE4 has been clearly pathogenic for decades, targeted therapeutic technologies remain in a blank state: The mechanism targeting is insufficient, and no medicine is interfered to reprogram or epigenetic abnormality of cholesterol metabolism mediated by APOE4, and the existing scheme only indirectly influences Abeta/tau pathology and does not touch the root cause of gene driving. Diagnosis and treatment dislocation, namely APOE4 gene detection is clinically popular, but the detection result cannot guide treatment-positive people can only reduce risks through life style intervention, and an effective drug prevention or delay means is lacked. Lack of population adaptation-existing drugs do not take into account physiological characteristics of APOE4 carriers (e.g., blood brain barrier permeability changes, elevated inflammatory baselines),