Matrix Metalloproteinase-9 Regulates Neuronal Circuit Development and Excitability

Murase, Sachiko; Lantz, Crystal L.; Kim, Eun Young; Gupta, Nitin; Higgins, Richard; Stopfer, Mark; Hoffman, Dax A.; Quinlan, Elizabeth

doi:10.1007/s12035-015-9295-y

Cited by 32 publications

(25 citation statements)

References 78 publications

(100 reference statements)

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“…Intercellular adhesion molecule-5 (ICAM-5), which mediates the regulation of dendritic spine elongation and maturation may be cleaved by MMP9 upon activation of N-methyl- d -aspartate (NMDA) receptors [23, 24], suggesting a role for MMP9 in synaptic function. Furthermore, MMP9 deletion increases the number of CA1 pyramidal neurons and decreases the length and complexity of dendritic spines [25]. Immune system dysfunction may develop with aging in parallel with upregulation of brain MMP9 [26–28].…”

Section: Discussionmentioning

confidence: 99%

Resveratrol regulates neuro-inflammation and induces adaptive immunity in Alzheimer’s disease

Moussa

Hebron

Huang

et al. 2017

J Neuroinflammation

564

398

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BackgroundTreatment of mild-moderate Alzheimer’s disease (AD) subjects (N = 119) for 52 weeks with the SIRT1 activator resveratrol (up to 1 g by mouth twice daily) attenuates progressive declines in CSF Aβ40 levels and activities of daily living (ADL) scores.MethodsFor this retrospective study, we examined banked CSF and plasma samples from a subset of AD subjects with CSF Aβ42 <600 ng/ml (biomarker-confirmed AD) at baseline (N = 19 resveratrol-treated and N = 19 placebo-treated). We utilized multiplex Xmap technology to measure markers of neurodegenerative disease and metalloproteinases (MMPs) in parallel in CSF and plasma samples.ResultsCompared to the placebo-treated group, at 52 weeks, resveratrol markedly reduced CSF MMP9 and increased macrophage-derived chemokine (MDC), interleukin (IL)-4, and fibroblast growth factor (FGF)-2. Compared to baseline, resveratrol increased plasma MMP10 and decreased IL-12P40, IL12P70, and RANTES. In this subset analysis, resveratrol treatment attenuated declines in mini-mental status examination (MMSE) scores, change in ADL (ADCS-ADL) scores, and CSF Aβ42 levels during the 52-week trial, but did not alter tau levels.ConclusionsCollectively, these data suggest that resveratrol decreases CSF MMP9, modulates neuro-inflammation, and induces adaptive immunity. SIRT1 activation may be a viable target for treatment or prevention of neurodegenerative disorders.Trial registrationClinicalTrials.gov NCT01504854

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Section: Discussionmentioning

confidence: 99%

Resveratrol regulates neuro-inflammation and induces adaptive immunity in Alzheimer’s disease

Moussa

Hebron

Huang

et al. 2017

J Neuroinflammation

564

398

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“…Additionally, MMP‐9 deletion significantly increased spontaneous neuronal activity in awake MMP‐9 knockout mice and enhanced the response to acute pro‐convulsive challenge (Murase et al . ).…”

Section: Research Tools To Study Mmp‐9 In Humans and Animalsmentioning

confidence: 97%

“…In a recent study, Murase et al . () reported that MMP‐9 deletion in mice increased the number of CA1 pyramidal neurons but decreased dendritic length and complexity. Furthermore, parallel changes in neuronal morphology in the primary visual cortex persisted into adulthood.…”

Section: Research Tools To Study Mmp‐9 In Humans and Animalsmentioning

confidence: 98%

MMP‐9 in translation: from molecule to brain physiology, pathology, and therapy

Vafadari

Salamian

Kaczmarek

2016

Journal of Neurochemistry

301

257

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Matrix metalloproteinase-9 (MMP-9) is a member of the metzincin family of mostly extracellularly operating proteases. Despite the fact that all of these enzymes might be target promiscuous, with largely overlapping catalogs of potential substrates, MMP-9 has recently emerged as a major and apparently unique player in brain physiology and pathology. The specificity of MMP-9 may arise from its very local and time-restricted actions, even when released in the brain from cells of various types, including neurons, glia, and leukocytes. In fact, the quantity of MMP-9 is very low in the naive brain, but it is markedly activated at the levels of enzymatic activity, protein abundance, and gene expression following various physiological stimuli and pathological insults. Neuronal MMP-9 participates in synaptic plasticity by controlling the shape of dendritic spines and function of excitatory synapses, thus playing a pivotal role in learning, memory, and cortical plasticity. When improperly unleashed, MMP-9 contributes to a large variety of brain disorders, including epilepsy, schizophrenia, autism spectrum disorder, brain injury, stroke, neurodegeneration, pain, brain tumors, etc. The foremost mechanism of action of MMP-9 in brain disorders appears to be its involvement in immune/inflammation responses that are related to the enzyme's ability to process and activate various cytokines and chemokines, as well as its contribution to bloodbrain barrier disruption, facilitating the extravasation of leukocytes into brain parenchyma. However, another emerging possibility (i.e., the control of MMP-9 over synaptic plasticity) should not be neglected. The translational potential of MMP-9 has already been recognized in both the diagnosis and treatment domains. The most striking translational aspect may be the discovery of MMP-9 up-regulation in a mouse model of Fragile X syndrome, quickly followed by human studies and promising clinical trials that have sought to inhibit MMP-9. With regard to diagnosis, suggestions have been made to use MMP-9 alone or combined with tissue inhibitor of matrix metalloproteinase-1 or brain-derived neurotrophic factor as disease biomarkers.

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“…By the end of the foetal period, PAX6 was gradually down‐regulated, whereas MMP‐9 was increased. In addition to an extensive role during migration, MMP‐9 is important for neurite formation and circuit development that occurs extensively between neurones in the IGL after migration and MMP‐9 is not down‐regulated until this process is completed in mature neurones . The slow‐onset down‐regulation of MMP‐9 seen after exposure to DEX may alter these processes.…”

Section: Discussionmentioning

confidence: 99%

Glucocorticoid Effects on Cerebellar Development in a Chicken Embryo Model: Exploring Changes in PAX6 and Metalloproteinase‐9 After Exposure to Dexamethasone

Austdal

Bjørnstad

Mathisen

et al. 2016

J Neuroendocrinology

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The developing cerebellum is vulnerable to effects of glucocorticoids and cerebellar dysfunction is associated with neurodevelopmental disorders (e.g. autism). Transcription factor PAX6 and matrix metalloproteinase-9 (MMP-9) are critical for normal cerebellar development and are highly expressed in migrating neurones. Alterations in MMP-9 and PAX6 are associated with altered cerebellar development. In the present study, we characterised the growth rate and development of the cortical layers, and further investigated how the levels of PAX6 and MMP-9, as well as glucocorticoid receptor (GR) and proliferating cell nuclear antigen (PCNA), change in the cerebellum during the foetal period [embryonic day (E)12-21] in chicken, which corresponds to the human perinatal period. Dexamethasone (DEX) was administered in ovo at E13 and E16, aiming to investigate how prenatal exposure to glucocorticoids interferes with normal development. DEX reduced foetal and cerebellar weight at E17 in a dose-dependent manner linked to a reduced level of PCNA and, over time, down-regulation of GR. We report that promoter activity of PAX6 and MMP-9 increased as a result of GR-stimulation in vitro. Prenatal DEX increased the protein level of PAX6 in a transient manner. PAX6 is reduced in mature granule neurones, and this occurred earlier in embryos exposed to DEX than in non-exposed controls. DEX exposure also led to a slow-onset down-regulation of MMP-9. Taken together, these findings indicate that excess prenatal glucocorticoid stimulation disturbs normal development of the cerebellum through mechanisms associated with reduced proliferation and accelerated maturation where PAX6 and MMP-9 play important roles.

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Matrix Metalloproteinase-9 Regulates Neuronal Circuit Development and Excitability

Cited by 32 publications

References 78 publications

Resveratrol regulates neuro-inflammation and induces adaptive immunity in Alzheimer’s disease

Resveratrol regulates neuro-inflammation and induces adaptive immunity in Alzheimer’s disease

MMP‐9 in translation: from molecule to brain physiology, pathology, and therapy

Glucocorticoid Effects on Cerebellar Development in a Chicken Embryo Model: Exploring Changes in PAX6 and Metalloproteinase‐9 After Exposure to Dexamethasone

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