Matrix Metalloproteinases as New Targets in Alzheimer’s Disease: Opportunities and Challenges

Zipfel, Pauline; Rochais, Christophe; Baranger, Kévin; Rivera, Santiago; Dallemagne, Patrick

doi:10.1021/acs.jmedchem.0c00352

Cited by 56 publications

(39 citation statements)

References 222 publications

(471 reference statements)

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“…Our current data suggest that MT5-MMP can also control inflammation per se in a non-pathological state in a human setting, but it remains an open question whether basal downregulation of inflammatory markers predisposes astrocytes to decreased reactivity. In any case, our results reinforce the idea that MT5-MMP is not only an APP-cleaving enzyme but also that its scope of activity goes far beyond that [ 12 , 13 , 14 ].…”

Section: Discussionsupporting

confidence: 85%

“…Matrix metalloproteinases (MMPs), enzymes controlling intracellular and extracellular amyloidogenic protein turnover, are associated with neurodegenerative diseases [ 11 , 12 ]. Recently, we shed light on MT5-MMP as just such a novel therapeutic target [ 12 , 13 , 14 ]. In good health, MT5-MMP is a multifunctional MMP with N-cadherin substrate specificity that is mainly expressed in developmental stages and remains high in adulthood in the hippocampus and cerebellum [ 15 , 16 , 17 , 18 ].…”

Section: Introductionmentioning

confidence: 99%

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Deficiency in MT5-MMP Supports Branching of Human iPSCs-Derived Neurons and Reduces Expression of GLAST/S100 in iPSCs-Derived Astrocytes

Arnst

Belio-Mairal

García-González

et al. 2021

Cells

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For some time, it has been accepted that the β-site APP cleaving enzyme 1 (BACE1) and the γ-secretase are two main players in the amyloidogenic processing of the β-amyloid precursor protein (APP). Recently, the membrane-type 5 matrix metalloproteinase (MT5-MMP/MMP-24), mainly expressed in the nervous system, has been highlighted as a new key player in APP-processing, able to stimulate amyloidogenesis and also to generate a neurotoxic APP derivative. In addition, the loss of MT5-MMP has been demonstrated to abrogate pathological hallmarks in a mouse model of Alzheimer’s disease (AD), thus shedding light on MT5-MMP as an attractive new therapeutic target. However, a more comprehensive analysis of the role of MT5-MMP is necessary to evaluate how its targeting affects neurons and glia in pathological and physiological situations. In this study, leveraging on CRISPR-Cas9 genome editing strategy, we established cultures of human-induced pluripotent stem cells (hiPSC)-derived neurons and astrocytes to investigate the impact of MT5-MMP deficiency on their phenotypes. We found that MT5-MMP-deficient neurons exhibited an increased number of primary and secondary neurites, as compared to isogenic hiPSC-derived neurons. Moreover, MT5-MMP-deficient astrocytes displayed higher surface area and volume compared to control astrocytes. The MT5-MMP-deficient astrocytes also exhibited decreased GLAST and S100β expression. These findings provide novel insights into the physiological role of MT5-MMP in human neurons and astrocytes, suggesting that therapeutic strategies targeting MT5-MMP should be controlled for potential side effects on astrocytic physiology and neuronal morphology.

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Section: Discussionsupporting

confidence: 85%

Section: Introductionmentioning

confidence: 99%

Deficiency in MT5-MMP Supports Branching of Human iPSCs-Derived Neurons and Reduces Expression of GLAST/S100 in iPSCs-Derived Astrocytes

Arnst

Belio-Mairal

García-González

et al. 2021

Cells

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“…The activated MMPs remodel the pericellular environment by regulating the extracellular matrix (ECM) and the tight junction's breakdown. The MMPs also interact and alter the properties of growth factors, cell surface components, and signaling molecules, leading to neuroinflammation, cell death, and neurotoxicity [50]. In this context, separate studies conducted by Duits et al, 2015 [51] and Whelan et al, 2019 [52] showed a significant increase in MMP-10 in AD-dementia Aβ+ MCI patients as compared to cognitively normal individuals.…”

Section: Discussionmentioning

confidence: 99%

An Ensemble-Learning Based Application to Predict the Earlier Stages of Alzheimer’s Disease (AD)

et al. 2020

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The fact that ensemble methods enhance the prediction performance. Therefore, we focused on developing a weighted ensemble method using a novel combination of Cerebrospinal Fluid (CSF) protein biomarkers to predict AD's earlier stages with greater accuracy than the stateof-the-art CSF protein biomarkers. In this regard, two feature selection methods, namely the Recursive Feature Elimination (RFE) and L1 regularization method were used to screen the most important subset of features for building a classification model using the Mild Cognitive Impairment (MCI) dataset. A novel combination of three biomarkers, namely Cystatin C, Matrix metalloproteinases (MMP10), and tau protein, was screened using the linear Support Vector Machine (SVM) and Logistic Regression (LR) classifier based RFE method. Two-tailed unpaired t-test analysis at a 5 % significance level showed a significant difference between the mean levels of Cystatin C, MMP10, and tau protein between cognitive normal and cognitively impaired groups. An ensemble model using a weighted average of two best performing classifiers (LR and Linear SVM) was created using a novel subset of three most informative features. Our ensemble model's weighted average results performed significantly better than LR and Linear SVM base classifiers' performance. The Receiver Operating Characteristic Curve (ROC_AUC) and Area under Precision-Recall values (AUPR) of our proposed model were observed to be 0.9799 ± 0.055 0.9108 ± 0.015, respectively. The performance of our proposed weighted averaged ensemble model built using a novel combination of CSF protein biomarkers was significantly better (p < 0.001) than models generated using different combinations of CSF protein biomarkers obtained from recent studies. An ensemble-learning based application was implemented and deployed at Heroku at https://appsalzheimer.herokuapp.com.

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“…Since then, selectivity has become one of the principal aspects of MMP inhibitor design. In addition, various molecules acting against two or more MMPs have recently been investigated, suggesting that carefully selected multitarget approaches also represent a promising strategy for targeting MMPs [16].…”

Section: Introductionmentioning

confidence: 99%

Natural Marine and Terrestrial Compounds as Modulators of Matrix Metalloproteinases-2 (MMP-2) and MMP-9 in Alzheimer’s Disease

et al. 2021

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Several studies have reported neuroprotective effects by natural products. A wide range of natural compounds have been investigated, and some of these may play a beneficial role in Alzheimer’s disease (AD) progression. Matrix metalloproteinases (MMPs), a family of zinc-dependent endopeptidases, have been implicated in AD. In particular, MMP-2 and MMP-9 are able to trigger several neuroinflammatory and neurodegenerative pathways. In this review, we summarize and discuss existing literature on natural marine and terrestrial compounds, as well as their ability to modulate MMP-2 and MMP-9, and we evaluate their potential as therapeutic compounds for neurodegenerative and neuroinflammatory diseases, with a focus on Alzheimer’s disease.

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Matrix Metalloproteinases as New Targets in Alzheimer’s Disease: Opportunities and Challenges

Cited by 56 publications

References 222 publications

Deficiency in MT5-MMP Supports Branching of Human iPSCs-Derived Neurons and Reduces Expression of GLAST/S100 in iPSCs-Derived Astrocytes

Deficiency in MT5-MMP Supports Branching of Human iPSCs-Derived Neurons and Reduces Expression of GLAST/S100 in iPSCs-Derived Astrocytes

An Ensemble-Learning Based Application to Predict the Earlier Stages of Alzheimer’s Disease (AD)

Natural Marine and Terrestrial Compounds as Modulators of Matrix Metalloproteinases-2 (MMP-2) and MMP-9 in Alzheimer’s Disease

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