CN-121971655-A - Adenovirus targeting microglial LPL and its use in tauopathy treatment

Abstract

The invention provides an adeno-associated virus targeting microglial cell LPL and application thereof in treating tauopathy, wherein the adeno-associated virus AAV vector is utilized to overexpress lipoprotein lipase LPL in microglial cells to treat tau-associated neurodegenerative diseases. According to the invention, by introducing a microglial cell specific promoter into an AAV vector, the humanized LPL gene is accurately delivered into microglial cells of specific brain regions of a central nervous system, so that lasting high-efficiency expression is realized. The strategy can enhance the capacity of microglial cells to decompose excessive lipid, reduce lipid drop load, inhibit chronic inflammatory reaction, and thus block malignant circulation of lipid drop deposition-inflammation-tau protein pathological exacerbation.

Inventors

• WANG CHAO
• DONG HONGWEI
• LIU YILIN

Assignees

• 重庆医科大学

Dates

Publication Date

20260505

Application Date

20260208

Claims (10)

1. 1. Use of an LPL agonist in microglia for the preparation of a medicament for preventing or treating a neurodegenerative disease-related disorder.
2. 2. The use according to claim 1, wherein the neurodegenerative related disease is a pathological tau related disease.
3. 3. The use of claim 2, wherein the pathological tau protein associated disease is alzheimer's disease, frontotemporal dementia, progressive supranuclear palsy, corticobasal degeneration, traumatic brain injury, or cognitive impairment.
4. 4. The use of any one of claims 1-3, wherein the use is one or more of decreasing phosphorylated Tau protein levels in the brain, decreasing microglial lipid droplet accumulation, decreasing neuroinflammatory response, increasing hippocampal or cortical volume to alleviate brain atrophy, improving cognitive function or daily motor capacity.
5. 5. An adeno-associated virus (AAV) vector for targeting microglial LPL is characterized in that a microglial specific promoter mIBA1 is introduced into the AAV vector, so that the human LPL gene is precisely delivered into microglial cells of specific brain regions of a central nervous system, and long-lasting high-efficiency expression is realized, wherein the microglial specific promoter sequence mIBA is shown as SEQ ID NO. 1.
6. 6. The vector of claim 5, wherein the sequence of the human LPL gene is set forth in SEQ ID No. 2.
7. 7. The vector of claim 5, further comprising a FLAG tag 3 x FLAG sequence, wherein the FLAG tag 3 x FLAG sequence is set forth in SEQ ID No. 3.
8. 8. A recombinant adeno-associated virus vector AAV 11-mIBA-Human-LPL-3 xFLAG virus vector comprises microglial cell specific promoter mIBA shown in SEQ ID NO.1, a Human LPL coding sequence shown in SEQ ID NO.2, and a FLAG tag 3 xFLAG sequence shown in SEQ ID NO. 3.
9. 9. The vector of any one of claims 5-8 for use in the treatment of a pathological tau-associated neurodegenerative related disease selected from the group consisting of Alzheimer's disease, frontotemporal dementia, progressive supranuclear palsy, corticobasal degeneration, traumatic brain injury, and cognitive impairment.
10. 10. The use of claim 9, wherein the use is one or more of decreasing phosphorylated Tau protein levels in the brain, decreasing microglial lipid droplet accumulation, decreasing neuroinflammatory response, increasing hippocampal or cortical volume to alleviate brain atrophy, improving cognitive function or daily motor capacity.

Description

Adenovirus targeting microglial LPL and its use in tauopathy treatment Technical Field The invention belongs to the technical field of biological medicines, relates to treatment of tauopathy, and in particular relates to application of specificity over-expression lipoprotein lipase in microglia by utilizing an adeno-associated virus vector to treatment of pathological tau protein-associated neurodegenerative disease-associated diseases. Background Alzheimer's Disease (AD) is the most common type of dementia, whose major neuropathological features include senile plaques formed by extracellular beta-amyloid (Abeta), neurofibrillary tangles due to aggregation of hyperphosphorylated tau protein within neurons, and synaptic loss and neuronal death in areas such as hippocampus, cerebral cortex, etc. The existing treatment means still mainly relieve symptoms, and have limited modification effects on disease processes. Therefore, it is of great importance to find new disease modifying therapeutic targets and develop intervention strategies with clinical transformation potential. Numerous studies have found that lipid metabolism abnormalities occur early in AD and accompany the progression of the disease through the process. In particular, in the context of tau pathology, neurons accumulate excessive amounts of unsaturated lipids and transfer these lipids to microglia, which thus form a large lipid droplet load, leading to increased secretion of inflammatory factors, decreased phagocytosis and thus exacerbation of neuronal damage. This process forms a vicious circle of "lipid droplet deposition-chronic inflammation-exacerbation of tau pathology". Lipoprotein lipase (Lipoprotein Lipase, LPL) is a key rate-limiting enzyme for hydrolyzing triglycerides, and is also an important molecule for maintaining lipid homeostasis in the brain. LPL is highly expressed in the hippocampus and is closely related to learning memory and synaptic plasticity, enhancing its function can reduce triglyceride level and lipid drop load, while LPL deficiency can promote neuroinflammation and impair Abeta clearance. Conventional LPL agonists are mainly expressed peripherally and are difficult to penetrate the blood brain barrier. In recent years, adeno-Associated Virus (AAV) has become one of the core vectors for central nervous system gene therapy and has been used for a variety of nervous system diseases that are difficult to rely on conventional drug therapy, including neurodegenerative diseases. AAV has the advantages of low immunogenicity, long-term stable expression, capability of infecting non-dividing cells, and the like, and serotype and capsid modification can realize accurate cell and tissue specific transduction. In neurological studies, AAV has successfully achieved targeted gene delivery to neurons, astrocytes and microglia. Disclosure of Invention Based on this, the present study innovatively designed AAV vectors of microglial-specific promoters for targeted overexpression of human LPL in the hippocampus of mice for the vicious circle caused by "neuronal-microglial lipid transfer" in tauopathies. The inventors have found and demonstrated for the first time that specific up-regulation of LPL function in microglial cells in a tauopathies model (such as PS19 mice) can significantly improve neurobehavioral defects, alleviate brain atrophy and alleviate neurodegenerative pathology. This reveals "up-regulating microglial LPL activity" as a completely new, universal therapeutic target for diseases. A first object of the present invention is to provide the use of an LPL agonist in microglia for the preparation of a medicament for preventing or treating a neurodegenerative related disease. The invention provides an application of an LPL agonist in microglia in preparation of medicines for preventing or treating neurodegenerative disease-related diseases. Preferably, the neurodegenerative disease-related disorder is a pathological Tau protein-related disorder such as alzheimer's disease, frontotemporal dementia, progressive supranuclear palsy, corticobasal degeneration, traumatic brain injury-related Tau lesions, and mild cognitive impairment characterized by pathological Tau proteins, and the like. In the present invention, the use is one or more of decreasing the levels of phosphorylated Tau protein in the brain, decreasing microglial lipid droplet accumulation, decreasing neuroinflammatory response, increasing hippocampal or cortical volume, alleviating brain atrophy, improving cognitive function or daily activity. Another object of the present invention is to provide an adeno-associated viral vector targeting microglial LPL, which is a novel therapeutic strategy for tauopathies with disease modification potential, and is characterized in that the expression of LPL in microglial cells of the central nervous system is specifically up-regulated by AAV-mediated gene delivery, thereby correcting lipid metabolism disorders, alleviating neur