Enhanced oxidative stress contributes to worse prognosis and delayed neurofunctional recovery after striatal intracerebral hemorrhage in 5XFAD mice

Hayashi, Kenyu; Hasegawa, Yu; Takemoto, Yushin; Cao, Cheng; Mukasa, Akitake; Kim‐Mitsuyama, Shokei

doi:10.1111/ejn.14596

Cited by 11 publications

(8 citation statements)

References 22 publications

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“…Alternatively, the degradation of laminin or other matrix proteins by MMP9 throughout the brain may disrupt cell-matrix interactions and play a role in neuronal cell death [24], which could be attenuated through MMP9 modulation. In fact, inhibition of MMP9 has been shown to reduce tissue damage, neutrophil infiltration, oxidative stress and degenerating neurons [7,25,26], all factors that could contribute to the impaired social memory in the 5xFAD mice [36,[75][76][77][78][79].…”

Section: Discussionmentioning

confidence: 99%

MMP9 modulation improves specific neurobehavioral deficits in a mouse model of Alzheimer’s disease

et al. 2021

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Background Matrix metallopeptidase 9 (MMP9) has been implicated in a variety of neurological disorders, including Alzheimer’s disease (AD), where MMP9 levels are elevated in the brain and cerebrovasculature. Previously our group demonstrated apolipoprotein E4 (apoE4) was less efficient in regulating MMP9 activity in the brain than other apoE isoforms, and that MMP9 inhibition facilitated beta-amyloid (Aβ) elimination across the blood–brain barrier (BBB) Methods In the current studies, we evaluated the impact of MMP9 modulation on Aβ disposition and neurobehavior in AD using two approaches, (1) pharmacological inhibition of MMP9 with SB-3CT in apoE4 x AD (E4FAD) mice, and (2) gene deletion of MMP9 in AD mice (MMP9KO/5xFAD) Results Treatment with the MMP9 inhibitor SB-3CT in E4FAD mice led to reduced anxiety compared to placebo using the elevated plus maze. Deletion of the MMP9 gene in 5xFAD mice also reduced anxiety using the open field test, in addition to improving sociability and social recognition memory, particularly in male mice, as assessed through the three-chamber task, indicating certain behavioral alterations in AD may be mediated by MMP9. However, neither pharmacological inhibition of MMP9 or gene deletion of MMP9 affected spatial learning or memory in the AD animals, as determined through the radial arm water maze. Moreover, the effect of MMP9 modulation on AD neurobehavior was not due to changes in Aβ disposition, as both brain and plasma Aβ levels were unchanged in the SB-3CT-treated E4FAD animals and MMP9KO/AD mice compared to their respective controls. Conclusions In total, while MMP9 inhibition did improve specific neurobehavioral deficits associated with AD, such as anxiety and social recognition memory, modulation of MMP9 did not alter spatial learning and memory or Aβ tissue levels in AD animals. While targeting MMP9 may represent a therapeutic strategy to mitigate aspects of neurobehavioral decline in AD, further work is necessary to understand the nature of the relationship between MMP9 activity and neurological dysfunction.

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Section: Discussionmentioning

confidence: 99%

MMP9 modulation improves specific neurobehavioral deficits in a mouse model of Alzheimer’s disease

et al. 2021

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“…[140][141][142][143][144][145][146] Others also established the role of free radicals in sICH-induced brain damage. [147][148][149] Because nicotine exposure increases the activation of pathways involved in post-sICH brain damage, it is plausible that elevated activation of those pathways is enhanced post-sICH, which in turn leads to increased brain damage.…”

Section: Potential Mechanisms By Which Tobacco Use Affects the Risk Of Sich And Outcome Following Sichmentioning

confidence: 99%

Tobacco Use: A Major Risk Factor of Intracerebral Hemorrhage

Cho

Rehni

2021

J Stroke

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Spontaneous intracerebral hemorrhage (sICH) is one of the deadliest subtypes of stroke, and no treatment is currently available. One of the major risk factors is tobacco use. In this article, we review literature on how tobacco use affects the risk of sICH and also summarize the known effects of tobacco use on outcomes following sICH. Several studies demonstrate that the risk of sICH is higher in current cigarette smokers compared to non-smokers. The literature also establishes that cigarette smoking not only increases the risk of sICH but also increases hematoma growth, results in worse outcomes, and increases the risk of death from sICH. This review also discusses potential mechanisms activated by tobacco use which result in an increase in risk and severity of sICH. Exploring the underlying mechanisms may help alleviate the risk of sICH in tobacco users as well as may help better manage tobacco user sICH patients.

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“…The 5xFAD mouse, a widely used AD mouse model, has 5 familiar AD-linked mutations, i.e., the Swedish (K670 N/ M671 L), Florida (I716V), and London (V717I) mutations in amyloid precursor protein (APP) and the M146 L and L286 V mutations in presenilin-1 (PSEN1) [2]. 5xFAD mice, characterized by cerebral amyloid plaques and gliosis, show massive Aβ 1-42 burdens from 2 months of age, declined synaptic markers from 4 months of age, and cognitive impairment from approximately 5 months of age [2][3][4][5]. Thus, pathological mechanisms of AD could be evaluated by analyzing biochemical changes in the brain in 5xFAD mice at different disease stages.…”

Section: Introductionmentioning

confidence: 99%

Nicotinamide attenuates the decrease in dendritic spine density in hippocampal primary neurons from 5xFAD mice, an Alzheimer’s disease animal model

Kim

Cho

2020

Mol Brain

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Alzheimer's disease (AD) is the most common neurodegenerative disease characterized by memory loss and the presence of amyloid plaques and neurofibrillary tangles in the patients' brains. In this study, we investigated the alterations in metabolite profiles of the hippocampal tissues from 6, 8, and 12 month-old wild-type (WT) and 5xfamiliar AD (5xFAD) mice, an AD mouse model harboring 5 early-onset familiar AD mutations, which shows memory loss from approximately 5 months of age, by exploiting the untargeted metabolomics profiling. We found that nicotinamide and adenosine monophosphate levels have been significantly decreased while lysophosphatidylcholine (LysoPC) (16:0), LysoPC (18:0), and lysophosphatidylethanolamine (LysoPE) (16:0) levels have been significantly increased in the hippocampi from 5xFAD mice at 8 months or 12 months of age, compared to those from age-matched wild-type mice. In the present study, we focused on the role of nicotinamide and examined if replenishment of nicotinamide exerts attenuating effects on the reduction in dendritic spine density in hippocampal primary neurons from 5xFAD mice. Treatment with nicotinamide attenuated the deficits in spine density in the hippocampal primary neurons derived from 5xFAD mice, indicating a potential role of nicotinamide in the pathogenesis of AD. Taken together, these findings suggest that the decreased hippocampal nicotinamide level could be linked with AD pathogenesis and be a useful therapeutic target for AD.

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Enhanced oxidative stress contributes to worse prognosis and delayed neurofunctional recovery after striatal intracerebral hemorrhage in 5XFAD mice

Cited by 11 publications

References 22 publications

MMP9 modulation improves specific neurobehavioral deficits in a mouse model of Alzheimer’s disease

MMP9 modulation improves specific neurobehavioral deficits in a mouse model of Alzheimer’s disease

Tobacco Use: A Major Risk Factor of Intracerebral Hemorrhage

Nicotinamide attenuates the decrease in dendritic spine density in hippocampal primary neurons from 5xFAD mice, an Alzheimer’s disease animal model

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