Omaveloxolone Ameliorates Cognitive Deficits by Inhibiting Apoptosis and Neuroinflammation in APP/PS1 Mice
Zhaojun Liu1, Jianping Jia2,3,4,5,6
1Innovation Center for Neurological Disorders and Department of Neurology, Xuanwu Hospital, Capital Medical University, National Clinical Research Center for Geriatric Diseases, Changchun Street 45, Beijing, PR China.
Abstract:
Alzheimer's disease (AD) is the most prevalent neurodegenerative disease associated with aging, characterized by progressive cognitive impairment and memory loss. However, treatments that delay AD progression or improve its symptoms remain limited. The aim of the present study was to investigate the therapeutic effects of omaveloxolone (Omav) on AD and to explore the underlying mechanisms. Thirty-week-old APP/PS1 mice were selected as an experimental model of AD. The spatial learning and memory abilities were tested using the Morris water maze. Amyloid-beta (Aβ) deposition in the brains was measured using immunohistochemistry. Network pharmacological analyses and molecular docking were conducted to gain insights into the therapeutic mechanisms of Omav. Finally, validation analyses were conducted to detect changes in the associated pathways and proteins. Our finding revealed that Omav markedly rescued cognitive dysfunction and reduced Aβ deposition in the brains of APP/PS1 mice. Network pharmacological analysis identified 112 intersecting genes, with CASP3 and MTOR emerging as the key targets. In vivo validation experiments indicated that Omav attenuated neuronal apoptosis by regulating apoptotic proteins, including caspase 3, Bax, and Bcl-2. Moreover, Omav suppressed neuroinflammation and induced autophagy by inhibiting the phosphorylation of mTOR. These findings highlight the therapeutic efficacy of Omav in AD and that its neuroprotective effects were associated with inhibiting neuronal apoptosis and regulating neuroinflammation.
Insights
Omaveloxolone (Omav) shows therapeutic potential for Alzheimer's disease (AD), significantly improving cognitive function and reducing amyloid-beta plaques in mouse models. It works by inhibiting neuronal apoptosis and neuroinflammation.
Area of Science:
- Neuroscience
- Pharmacology
- Gerontology
Background:
- Alzheimer's disease (AD) is a leading cause of age-related neurodegeneration, marked by cognitive decline.
- Current treatments for AD offer limited efficacy in delaying disease progression or alleviating symptoms.
Purpose of the Study:
- To investigate the therapeutic effects of omaveloxolone (Omav) on Alzheimer's disease (AD).
- To elucidate the underlying molecular mechanisms of Omav's action in an AD model.
Main Methods:
- Utilized APP/PS1 transgenic mice as an AD model.
- Assessed cognitive function using the Morris water maze.
- Quantified amyloid-beta (Aβ) deposition via immunohistochemistry.
- Employed network pharmacology and molecular docking to identify therapeutic targets.
- Conducted in vivo validation for pathway and protein analysis.
Main Results:
- Omaveloxolone (Omav) significantly improved spatial learning and memory in APP/PS1 mice.
- Omav treatment markedly reduced amyloid-beta (Aβ) deposition in the brain.
- Network analysis identified CASP3 and MTOR as key targets.
- Omav attenuated neuronal apoptosis by modulating caspase 3, Bax, and Bcl-2.
- Omav suppressed neuroinflammation and induced autophagy via mTOR pathway inhibition.
Conclusions:
- Omaveloxolone demonstrates significant therapeutic efficacy in an Alzheimer's disease mouse model.
- Neuroprotective effects are attributed to the inhibition of neuronal apoptosis and regulation of neuroinflammation.
- Omav holds promise as a potential treatment for Alzheimer's disease.
