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OAB-14 Effectively Ameliorates the Dysfunction of the Endosomal-Autophagic-Lysosomal Pathway in APP/PS1 Transgenic
Xiaoli Guo1, Xuefei Bao2, Xiaojuan Wang1
1Department of Pharmacology, Life Science and Biopharmaceutics School, Shenyang Pharmaceutical University, 103 Wenhua Road, Shenyang, Liaoning 110016, P. R. China.
Abstract:
In Alzheimer's disease (AD), damaged Aβ clearance contributes to elevated levels of Aβ that cause a series of cytotoxic cascade reactions. Thus, targeting Aβ clearance has now been considered a valid therapeutic approach for AD. Cellular uptake and degradation are important mechanisms for Aβ clearance, which are mainly performed by the endosomal-autophagic-lysosomal (EAL) pathway. Our previous study showed that OAB-14, a novel small molecule designed with bexarotene as the lead compound, treatment for 3 months significantly alleviated cognitive disorders and remarkably reduced the deposition of Aβ without affecting its production in APP/PS1 transgenic mice. Here, we further revealed that enhancement of the EAL activity is one of the mechanisms that increases Aβ clearance after OAB-14 administration for 3 months. OAB-14 facilitates receptor-mediated endocytosis and restores autophagy flux via the AMPK/mTOR pathway. Meanwhile, OAB-14 enhances the lysosomal activity, and reduced Aβ accumulation in lysosomes was observed in OAB-14-treated AD mice. These results suggest that OAB-14 may promote Aβ clearance in lysosomes by alleviating the EAL dysfunction in AD mice.
Insights
OAB-14 enhances Alzheimer's disease clearance by improving the endosomal-autophagic-lysosomal pathway. This small molecule treatment reduces amyloid-beta accumulation and alleviates cognitive deficits in mice.
Area of Science:
- Neuroscience
- Pharmacology
- Cell Biology
Background:
- Alzheimer's disease (AD) is characterized by the accumulation of amyloid-beta (Aβ) due to impaired clearance.
- Targeting Aβ clearance presents a promising therapeutic strategy for AD.
- The endosomal-autophagic-lysosomal (EAL) pathway is crucial for cellular Aβ degradation.
Purpose of the Study:
- To investigate the mechanism by which OAB-14 enhances Aβ clearance in Alzheimer's disease models.
- To elucidate the role of the EAL pathway in OAB-14's therapeutic effects.
Main Methods:
- Treatment of APP/PS1 transgenic mice with OAB-14 for 3 months.
- Assessment of cognitive function and Aβ deposition.
- Analysis of EAL pathway activity, including receptor-mediated endocytosis, autophagy flux (AMPK/mTOR pathway), and lysosomal function.
Main Results:
- OAB-14 treatment significantly alleviated cognitive impairments and reduced Aβ deposition in AD mice.
- OAB-14 enhanced EAL pathway activity by facilitating receptor-mediated endocytosis.
- OAB-14 restored autophagy flux via the AMPK/mTOR pathway and improved lysosomal function, leading to reduced Aβ accumulation in lysosomes.
Conclusions:
- OAB-14 promotes Aβ clearance in Alzheimer's disease by enhancing the EAL pathway.
- OAB-14's mechanism involves restoring autophagy and improving lysosomal degradation of Aβ.
- OAB-14 represents a potential therapeutic agent for AD by targeting Aβ clearance mechanisms.
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