Dimethyl Fumarate is a Potential Therapeutic Option for Alzheimer's Disease
Xiaodi Sun1, Xinjun Suo1, Xianyou Xia2
1Department of Radiology and Tianjin Key Laboratoryof Functional Imaging, Tianjin Medical University General Hospital, Tianjin, P.R. China.
Background:
Dimethyl fumarate (DMF) has been approved for clinical treatment of multiple sclerosis based on its antioxidant and anti-inflammatory effects by activating the Nrf2 pathway. Since both oxidative stress and inflammation are involved in Alzheimer's disease (AD), DMF is a potential therapeutic option for AD.
Objective:
This study aims to test the therapeutic effects of DMF on AD model mice and to reveal its underlying molecular mechanisms.
Methods:
Cell viability assay and in vitro immunofluorescence imaging were used to evaluate the antioxidant effect of DMF on embryonic mouse hippocampal neurons. Behavioral test and brain magnetic resonance imaging were used to assess the therapeutic effects of DMF on spatial learning and memory as well as hippocampal volume in AD model mice with and without Nrf2 knockdown. Western blotting was used to analyze the expression of antioxidant enzymes and molecules associated with AD-related pathological pathways.
Results:
DMF inhibits reactive oxygen species overproduction and protects neurons without Nrf2 knockdown from death. DMF reduces amyloid-β induced memory impairment and hippocampal atrophy in AD model mice rather than in Nrf2 knockdown AD mice. DMF delays the progression of AD by activating the Nrf2 pathway to enhance the expression of downstream antioxidant enzymes and inhibits lipid peroxidation, apoptosis, inflammation, mitochondrial dysfunction and amyloid-β deposition.
Conclusion:
These results indicate that DMF is a potential therapeutic option for AD through its antioxidant, anti-inflammatory, anti-apoptotic, and other anti-AD effects by activating the Nrf2 pathway.
Insights
Dimethyl fumarate (DMF) shows therapeutic potential for Alzheimer's disease (AD) by activating the Nrf2 pathway. This treatment reduces oxidative stress and inflammation, improving cognitive function and mitigating AD progression in mice.
Area of Science:
- Neuroscience
- Pharmacology
- Biochemistry
Background:
- Dimethyl fumarate (DMF) is approved for multiple sclerosis treatment due to its Nrf2-mediated antioxidant and anti-inflammatory actions.
- Oxidative stress and inflammation are key contributors to Alzheimer's disease (AD) pathogenesis.
Purpose of the Study:
- To investigate the therapeutic efficacy of DMF in a mouse model of Alzheimer's disease.
- To elucidate the molecular mechanisms underlying DMF's effects in AD.
Main Methods:
- In vitro assays (cell viability, immunofluorescence) assessed DMF's antioxidant effects on neurons.
- In vivo studies utilized behavioral tests and MRI in AD model mice (with and without Nrf2 knockdown).
- Western blotting analyzed antioxidant enzyme expression and AD-related pathways.
Main Results:
- DMF protected neurons from death by inhibiting reactive oxygen species (ROS) in a Nrf2-dependent manner.
- DMF ameliorated memory deficits and hippocampal atrophy in AD mice, effects absent in Nrf2 knockdown models.
- DMF activation of Nrf2 enhanced antioxidant enzymes, reducing lipid peroxidation, apoptosis, inflammation, and amyloid-β deposition.
Conclusions:
- DMF demonstrates significant therapeutic potential for Alzheimer's disease.
- Nrf2 pathway activation is crucial for DMF's neuroprotective and anti-AD effects.
- DMF exhibits multifaceted benefits including antioxidant, anti-inflammatory, and anti-apoptotic properties relevant to AD treatment.
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