Dimethyl fumarate does not mitigate cognitive decline and β-amyloidosis in female APPPS1 mice

Möhle, Luisa; Brackhan, Mirjam; Bascuñana, Pablo; Pahnke, Jens

doi:10.1016/j.brainres.2021.147579

Cited by 15 publications

(16 citation statements)

References 63 publications

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“…El-Fatah et al showed that DMF improved cognitive deficits and reduced neuroinflammation in d -galactose-treated ovariectomized (OVX) rats in a postmenopausal dementia model [ 43 ]. In contrast, Mohle and colleagues reported that DMF did not reduce cognitive decline and amyloid-β deposition in female APP/PS1 mice [ 26 , 44 ]. Differences in the results among these studies, including ours, may be attributed to the use of different mouse models, the protocol of DMF administration (dose and duration), and the methods used for assessing cognitive function.…”

Section: Discussionmentioning

confidence: 99%

“…Dimethyl fumarate (DMF), an approved drug for multiple sclerosis, can disrupt the KEAP1–Nrf2 interaction by binding to cysteine residues within KEAP1, allowing Nrf2 translocation to the nucleus and Nrf2 transactivation of target genes by binding to their AREs [ 23 ]. Although DMF has been shown to be beneficial in models of neurodegenerative diseases, such as Parkinson’s disease and Huntington’s disease [ 24 , 25 ], the results were not consistent in DMF-administered mouse models of AD [ 10 , 26 ]. Therefore, whether DMF-mediated activation of the Nrf2 pathway confers neuroprotection in mice with AD by controlling neuroinflammation and its detailed molecular basis remains to be determined.…”

Section: Introductionmentioning

confidence: 99%

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Dimethyl fumarate improves cognitive impairment and neuroinflammation in mice with Alzheimer’s disease

Wang,

Sobue,

Watanabe

et al. 2024

J Neuroinflammation

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Background Neuroinflammation substantially contributes to the pathology of Alzheimer’s disease (AD), the most common form of dementia. Studies have reported that nuclear factor erythroid 2-related factor 2 (Nrf2) attenuates neuroinflammation in the mouse models of neurodegenerative diseases, however, the detailed mechanism remains unclear. Methods The effects of dimethyl fumarate (DMF), a clinically used drug to activate the Nrf2 pathway, on neuroinflammation were analyzed in primary astrocytes and AppNL−G−F (App-KI) mice. The cognitive function and behavior of DMF-administrated App-KI mice were evaluated. For the gene expression analysis, microglia and astrocytes were directly isolated from the mouse cerebral cortex by magnetic-activated cell sorting, followed by quantitative PCR. Results DMF treatment activated some Nrf2 target genes and inhibited the expression of proinflammatory markers in primary astrocytes. Moreover, chronic oral administration of DMF attenuated neuroinflammation, particularly in astrocytes, and reversed cognitive dysfunction presumably by activating the Nrf2-dependent pathway in App-KI mice. Furthermore, DMF administration inhibited the expression of STAT3/C3 and C3 receptor in astrocytes and microglia isolated from App-KI mice, respectively, suggesting that the astrocyte–microglia crosstalk is involved in neuroinflammation in mice with AD. Conclusion The activation of astrocytic Nrf2 signaling confers neuroprotection in mice with AD by controlling neuroinflammation, particularly by regulating astrocytic C3-STAT3 signaling. Furthermore, our study has implications for the repositioning of DMF as a drug for AD treatment.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Dimethyl fumarate improves cognitive impairment and neuroinflammation in mice with Alzheimer’s disease

Wang,

Sobue,

Watanabe

et al. 2024

J Neuroinflammation

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“…So far, the results from only one study are in contrast with the results obtained by our team and the findings cited above. Möhle et al [ 60 ] demonstrated that the DMF treatment did not ameliorate spatial memory deficits assessed in the MWM and neuroinflammatory processes in the APP/PS1 transgenic mouse model of AD. The authors justified the discrepancies of the results with previous studies by highlighting differences in the models’ characteristics, i.e., blood-brain barrier (BBB) integrity or its disruption, which can facilitate drug penetration into the brain.…”

Section: Discussionmentioning

confidence: 99%

“…The authors justified the discrepancies of the results with previous studies by highlighting differences in the models’ characteristics, i.e., blood-brain barrier (BBB) integrity or its disruption, which can facilitate drug penetration into the brain. The STZ-ICV was shown to damage the BBB [ 61 ], whereas, in the model of AD that was similar to that used by Möhle et al [ 60 ], there was no disruption of the BBB in 6-month-old mice [ 62 ]. However, older APP/PS1 mice (12-month-old) showed an impairment in the BBB [ 63 ].…”

Section: Discussionmentioning

confidence: 99%

Dimethyl Fumarate Alleviates Adult Neurogenesis Disruption in Hippocampus and Olfactory Bulb and Spatial Cognitive Deficits Induced by Intracerebroventricular Streptozotocin Injection in Young and Aged Rats

Kurowska

Ruciński

Myślińska

et al. 2022

IJMS

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The disorder of adult neurogenesis is considered an important mechanism underlying the learning and memory impairment observed in Alzheimer’s disease (AD). The sporadic nonhereditary form of AD (sAD) affects over 95% of AD patients and is related to interactions between genetic and environmental factors. An intracerebroventricular injection of streptozotocin (STZ-ICV) is a representative and well-established method to induce sAD-like pathology. Dimethyl fumarate (DMF) has antioxidant and anti-inflammatory properties and is used for multiple sclerosis treatment. The present study determines whether a 26-day DMF therapy ameliorates the disruption of adult neurogenesis and BDNF-related neuroprotection in the hippocampus and olfactory bulb (OB) in an STZ-ICV rat model of sAD. Considering age as an important risk factor for developing AD, this study was performed using 3-month-old (the young group) and 22-month-old (the aged group) male Wistar rats. Spatial cognitive functions were evaluated with the Morris water maze task. Immunofluorescent labelling was used to assess the parameters of adult neurogenesis and BDNF-related neuroprotection in the hippocampus and OB. Our results showed that the STZ-ICV evoked spatial learning and memory impairment and disturbances in adult neurogenesis and BDNF expression in both examined brain structures. In the aged animals, the deficits were more severe. We found that the DMF treatment significantly alleviated STZ-ICV-induced behavioural and neuronal disorders in both age groups of the rats. Our findings suggest that DMF, due to its beneficial effect on the formation of new neurons and BDNF-related neuroprotection, may be considered as a promising new therapeutic agent in human sAD.

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“…Formalin-fixed hemispheres were embedded in paraffin and cut into 4-μm-thick coronal sections using a rotation microtome (HM355S, Leica Biosystems GmbH, Nußloch, Germany) as described previously [ 75 , 76 , 77 , 204 , 205 , 206 , 207 , 208 , 209 , 210 ]. Sections (bregma +0.8 mm and −1.8 mm) were stained for microglia (IBA1, 1:1000, FUJIFILM Wako Chemicals Europe GmbH, 019–19741), astrocytes (GFAP, 1:500, Agilent, Santa Clara, CA, USA, Z033401-2) using a BOND-III ® automated immunostaining system (Leica Biosystems GmbH, Nußloch, Germany) with a hematoxylin counterstain (provided with the staining kit, Bond Polymer Refine Detection, DS9800).…”

Section: Methodsmentioning

confidence: 99%

A Novel Huntington’s Disease Assessment Platform to Support Future Drug Discovery and Development

Möhle

Brüning

et al. 2022

IJMS

Self Cite

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Huntington’s disease (HD) is a lethal neurodegenerative disorder without efficient therapeutic options. The inefficient translation from preclinical and clinical research into clinical use is mainly attributed to the lack of (i) understanding of disease initiation, progression, and involved molecular mechanisms; (ii) knowledge of the possible HD target space and general data awareness; (iii) detailed characterizations of available disease models; (iv) better suitable models; and (v) reliable and sensitive biomarkers. To generate robust HD-like symptoms in a mouse model, the neomycin resistance cassette was excised from zQ175 mice, generating a new line: zQ175Δneo. We entirely describe the dynamics of behavioral, neuropathological, and immunohistological changes from 15–57 weeks of age. Specifically, zQ175Δneo mice showed early astrogliosis from 15 weeks; growth retardation, body weight loss, and anxiety-like behaviors from 29 weeks; motor deficits and reduced muscular strength from 36 weeks; and finally slight microgliosis at 57 weeks of age. Additionally, we collected the entire bioactivity network of small-molecule HD modulators in a multitarget dataset (HD_MDS). Hereby, we uncovered 358 unique compounds addressing over 80 different pharmacological targets and pathways. Our data will support future drug discovery approaches and may serve as useful assessment platform for drug discovery and development against HD.

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Dimethyl fumarate does not mitigate cognitive decline and β-amyloidosis in female APPPS1 mice

Cited by 15 publications

References 63 publications

Dimethyl fumarate improves cognitive impairment and neuroinflammation in mice with Alzheimer’s disease

Dimethyl fumarate improves cognitive impairment and neuroinflammation in mice with Alzheimer’s disease

Dimethyl Fumarate Alleviates Adult Neurogenesis Disruption in Hippocampus and Olfactory Bulb and Spatial Cognitive Deficits Induced by Intracerebroventricular Streptozotocin Injection in Young and Aged Rats

A Novel Huntington’s Disease Assessment Platform to Support Future Drug Discovery and Development

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