Amelioration of Behavioral Impairments and Neuropathology by Antiepileptic Drug Topiramate in a Transgenic Alzheimer’s Disease Model Mice, APP/PS1

Owona, Brice Ayissi; Zug, Caroline; Schluesener, Hermann J.; Zhang, Zhi Yuan

doi:10.3390/ijms20123003

Cited by 14 publications

(8 citation statements)

References 38 publications

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“…AD is one of the most common age-linked neurodegenerative diseases causing dementia. The aggregation of Aβ peptides in the brain is the predominant pathological hallmark of AD ( 26 ). APP/PS1 AD model mice were double-transfected with the human APP695swe and the human PS1dE9 mutation, both of which are associated with early-onset AD ( 27 ).…”

Section: Discussionmentioning

confidence: 99%

Dl‑3‑n‑butylphthalide alleviates cognitive impairment in amyloid precursor protein/presenilin 1 transgenic mice by regulating the striatal‑enriched protein tyrosine phosphatase/ERK/cAMP‑response element‑binding protein signaling pathway

Zhao

Yang

et al. 2022

Exp Ther Med

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Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by cognitive impairment and the deposition of amyloid plaques in the brain. In a transgenic mouse model of AD, cognitive impairment and synaptic dysfunction were revealed to be associated with soluble amyloid oligomers and to occur prior to plaque formation. The results of our previous studies revealed that striatal-enriched protein tyrosine phosphatase (STEP) 61 negatively regulated the β-amyloid protein-mediated ERK/cAMP-response element-binding protein (CREB) signaling pathway. Dl-3-n-butylphthalide (NBP) is a synthetic compound approved by the Food and Drug Administration of China for the treatment of ischemic stroke in 2002. Studies have shown that the neuroprotective effects of NBP involve multiple mechanisms. The present study further explored the mechanism of NBP therapy in amyloid precursor protein (APP)/presenilin 1 (PS1) transgenic mice, and the involvement of the STEP/ERK/CREB signaling pathway. The results suggested that NBP treatment effectively ameliorated the spatial learning and memory impairment of the APP/PS1 transgenic mice, which was assessed using a Morris water maze. In addition, NBP reduced amyloid-induced activation of STEP 61 levels, while increasing phosphorylated (p)-ERK1/2 and p-CREB levels in the cerebral cortex and hippocampus of APP/PS1 transgenic mice by western blotting and immunostaining. In conclusion, the present study provided evidence to suggest that the new drug NBP improved amyloid-induced learning and memory deficits, likely through the regulation of the STEP/ERK/CREB pathway. The results revealed that NBP, as a multi-target drug, may exert a neuroprotective effect. Therefore, NBP may serve as an effective treatment for AD.

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Section: Discussionmentioning

confidence: 99%

Dl‑3‑n‑butylphthalide alleviates cognitive impairment in amyloid precursor protein/presenilin 1 transgenic mice by regulating the striatal‑enriched protein tyrosine phosphatase/ERK/cAMP‑response element‑binding protein signaling pathway

Zhao

Yang

et al. 2022

Exp Ther Med

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“…Our mouse model exhibits very aggressive AD-like pathology, from 3 to 7 months of ages the development of Aβ deposits presents an exponential growth pattern, the pathological changes at 5 months of age are already well developed [92]. The current study thereby mainly explores early and mid-term drug interventions for AD.…”

Section: Discussionmentioning

confidence: 99%

Zerumbone ameliorates behavioral impairments and neuropathology in transgenic APP/PS1 mice by suppressing MAPK signaling

Zhao

et al. 2020

J Neuroinflammation

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Background: Alzheimer's disease (AD) is a major clinical problem, but there is a distinct lack of effective therapeutic drugs for this disease. We investigated the potential therapeutic effects of zerumbone, a subtropical ginger sesquiterpene, in transgenic APP/PS1 mice, rodent models of AD which exhibit cerebral amyloidosis and neuroinflammation. Methods: The N9 microglial cell line and primary microglial cells were cultured to investigate the effects of zerumbone on microglia. APP/PS1 mice were treated with zerumbone, and non-cognitive and cognitive behavioral impairments were assessed and compared between the treatment and control groups. The animals were then sacrificed, and tissues were collected for further analysis. The potential therapeutic mechanism of zerumbone and the signaling pathways involved were also investigated by RT-PCR, western blot, nitric oxide detection, enzyme-linked immunosorbent assay, immunohistochemistry, immunofluorescence, and flow cytometry analysis. Results: Zerumbone suppressed the expression of pro-inflammatory cytokines and induced a switch in microglial phenotype from the classic inflammatory phenotype to the alternative anti-inflammatory phenotype by inhibiting the mitogen-activated protein kinase (MAPK)/nuclear factor-kappa B signaling pathway in vitro. After a treatment period of 20 days, zerumbone significantly ameliorated deficits in both non-cognitive and cognitive behaviors in transgenic APP/PS1 mice. Zerumbone significantly reduced β-amyloid deposition and attenuated pro-inflammatory microglial activation in the cortex and hippocampus. Interestingly, zerumbone significantly increased the proportion of anti-inflammatory microglia among all activated microglia, potentially contributing to reduced β-amyloid deposition by enhancing phagocytosis. Meanwhile, zerumbone also reduced the expression of key molecules of the MAPK pathway, such as p38 and extracellular signal-regulated kinase. Conclusions: Overall, zerumbone effectively ameliorated behavioral impairments, attenuated neuroinflammation, and reduced β-amyloid deposition in transgenic APP/PS1 mice. Zerumbone exhibited substantial anti-inflammatory activity in microglial cells and induced a phenotypic switch in microglia from the pro-inflammatory phenotype to the antiinflammatory phenotype by inhibiting the MAPK signaling pathway, which may play an important role in its neuroprotective effects. Our results suggest that zerumbone is a potential therapeutic agent for human neuroinflammatory and neurodegenerative diseases, in particular AD.

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“…for 21 days [ 127 ]—30 mg/kg/day i.p. for 4 weeks Topiramate (TPM) APPswe/PS1dE9 [ 74 , 126 ] Decreased neuritic plaque [ 74 , 126 ] Reversed behavioral deficits [ 74 ] Upregulated Aβ transport across the BBB [ 74 ] Reduced tau phosphorylation [ 74 ] Increased frequency of interactive behavior and nest building activity [ 126 ] [ 74 ]—20 mg/kg, i.p. q.i.d.…”

Section: Preclinical Models Of Aging and Epilepsy Should Address Clinical Needsmentioning

confidence: 99%

“…q.i.d. for 30 days [ 126 ]—20 mg/kg, p.o. for 21 days Levetiracetam (LEV) APPswe/PS1dE9 [ 72 , 74 ] hAPPJ20 [ 23 ] 3xTg-AD [ 128 ] 5xFAD [ 129 ] Decreased neuritic plaque [ 74 ] Reversed behavioral deficits [ 23 , 74 ] Upregulated Aβ transport across the BBB [ 74 ] Reduced tau phosphorylation [ 74 ] Effective in reducing spike/seizure-indicating spike frequency [ 23 , 72 ] Improved learning and memory [ 23 ] Reversed synaptic deficits in hippocampus [ 23 ] Reversed the frequency-dependent reduced firing rates of cortical pyramidal cells and promoted uncoupling of inhibitory interneurons and pyramidal cells in cortex [ 128 ] Did not reduce levels of hAPP or Aβ [ 23 ] Loss of antiepileptic effect at high doses [ 23 ] Not able to rescue memory deficits [ 129 ] [ 72 ]—single dose of 75 mg/kg, i.p.…”

Section: Preclinical Models Of Aging and Epilepsy Should Address Clinical Needsmentioning

confidence: 99%

Alzheimer’s Disease and Epilepsy: A Perspective on the Opportunities for Overlapping Therapeutic Innovation

Lehmann

Knox

et al. 2021

Neurochem Res

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Early-onset Alzheimer’s disease (AD) is associated with variants in amyloid precursor protein (APP) and presenilin (PSEN) 1 and 2. It is increasingly recognized that patients with AD experience undiagnosed focal seizures. These AD patients with reported seizures may have worsened disease trajectory. Seizures in epilepsy can also lead to cognitive deficits, neuroinflammation, and neurodegeneration. Epilepsy is roughly three times more common in individuals aged 65 and older. Due to the numerous available antiseizure drugs (ASDs), treatment of seizures has been proposed to reduce the burden of AD. More work is needed to establish the functional impact of seizures in AD to determine whether ASDs could be a rational therapeutic strategy. The efficacy of ASDs in aged animals is not routinely studied, despite the fact that the elderly represents the fastest growing demographic with epilepsy. This leaves a particular gap in understanding the discrete pathophysiological overlap between hyperexcitability and aging, and AD more specifically. Most of our preclinical knowledge of hyperexcitability in AD has come from mouse models that overexpress APP. While these studies have been invaluable, other drivers underlie AD, e.g. PSEN2. A diversity of animal models should be more frequently integrated into the study of hyperexcitability in AD, which could be particularly beneficial to identify novel therapies. Specifically, AD-associated risk genes, in particular PSENs, altogether represent underexplored contributors to hyperexcitability. This review assesses the available studies of ASDs administration in clinical AD populations and preclinical studies with AD-associated models and offers a perspective on the opportunities for further therapeutic innovation.

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Amelioration of Behavioral Impairments and Neuropathology by Antiepileptic Drug Topiramate in a Transgenic Alzheimer’s Disease Model Mice, APP/PS1

Cited by 14 publications

References 38 publications

Dl‑3‑n‑butylphthalide alleviates cognitive impairment in amyloid precursor protein/presenilin 1 transgenic mice by regulating the striatal‑enriched protein tyrosine phosphatase/ERK/cAMP‑response element‑binding protein signaling pathway

Dl‑3‑n‑butylphthalide alleviates cognitive impairment in amyloid precursor protein/presenilin 1 transgenic mice by regulating the striatal‑enriched protein tyrosine phosphatase/ERK/cAMP‑response element‑binding protein signaling pathway

Zerumbone ameliorates behavioral impairments and neuropathology in transgenic APP/PS1 mice by suppressing MAPK signaling

Alzheimer’s Disease and Epilepsy: A Perspective on the Opportunities for Overlapping Therapeutic Innovation

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