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Targeting the miR-96-5p/Cathepsin B Pathway to Alleviate Neuron-Derived Neuroinflammation in Alzheimer's Disease
Kai Zheng1, He-Zhou Huang2, Dan Liu2
1Department of Geriatrics Tongji Hospital Tongji Medical College Huazhong University of Science and Technology Wuhan China.
Insights
Alzheimer's disease involves elevated Cathepsin B (CTSB), regulated by miR-96-5p. This pathway shows diagnostic potential for cognitive impairment and offers a therapeutic target for Alzheimer's disease.
Area of Science:
- Neuroscience
- Biochemistry
- Genetics
Background:
- Alzheimer's disease (AD) is a leading cause of dementia with no effective treatments.
- Cathepsin B (CTSB) plays a role in AD pathology, but its mechanisms and diagnostic/therapeutic relevance are unclear.
- The miR-96-5p/CTSB signaling pathway's role in AD needs further investigation.
Purpose of the Study:
- To investigate the role of the miR-96-5p/CTSB signaling pathway in Alzheimer's disease.
- To evaluate the diagnostic potential of serum miR-96-5p and CTSB in cognitive impairment.
- To explore the therapeutic potential of targeting the miR-96-5p/CTSB pathway in AD.
Main Methods:
- Assessed CTSB expression in the hippocampus of 3×Tg mice.
- Analyzed miR-96-5p and CTSB levels in serum from mild cognitive impairment and AD patients.
- Investigated the extracellular release of neuronal CTSB and its effect on astrocytes.
- Evaluated the therapeutic effect of restoring the miR-96-5p/CTSB pathway in AD models.
Main Results:
- CTSB expression was elevated in the hippocampus of 3×Tg mice and regulated by miR-96-5p.
- Serum miR-96-5p and CTSB abnormalities were detected in mild cognitive impairment and AD patients, showing diagnostic efficacy (AUC = 0.7536).
- Neuronal CTSB can be released extracellularly, reactivating adjacent astrocytes and potentially contributing to memory impairment.
- Restoring the miR-96-5p/CTSB pathway rescued astrocyte reactivity and memory deficits in AD models.
Conclusions:
- The neuron-derived inflammatory mediator CTSB reactivates astrocytes and contributes to memory impairment in early AD.
- Serum miR-96-5p and CTSB are potential biomarkers for diagnosing cognitive impairment.
- Targeting the neuronal miR-96-5p/CTSB pathway presents a promising therapeutic strategy for Alzheimer's disease.
Abstract:
Alzheimer's disease (AD) is one of the leading causes of dementia in the elderly, and no effective treatment is currently available. Cathepsin B (CTSB) is involved in key pathological processes of AD, but the underlying mechanisms and its relevance to AD diagnosis and treatment remain unclear. In the present study, we found that CTSB expression was abnormally elevated in the hippocampus of 3×Tg mice and was regulated by miR-96-5p. Abnormalities in the miR-96-5p/CTSB signaling pathway were detected in the serum of both mild cognitive impairment and AD patients, and the combination of serum miR-96-5p and CTSB demonstrated strong diagnostic efficacy for cognitive impairment (AUC = 0.7536). Abnormalities in the miR-96-5p/CTSB signaling pathway in AD may be associated with Aβ pathology, and neuronal CTSB can be released extracellularly to reactivate adjacent astrocytes. Ultimately, the reconstitution of the miR-96-5p/CTSB signaling pathway effectively rescued astrocyte reactivity and memory impairment in AD. Our findings suggest that the neuron-derived inflammatory mediator CTSB reactivates adjacent astrocytes and mediates memory impairment in early AD. The combination of serum miR-96-5p and CTSB represents potential serum biomarkers for cognitive impairment, and targeting the neuronal miR-96-5p/CTSB pathway may serve as a promising therapeutic strategy for AD.
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