A Path Toward Precision Medicine for Neuroinflammatory Mechanisms in Alzheimer's Disease
Neuroinflammation commences decades before Alzheimer's disease (AD) clinical onset and represents one of the earliest pathomechanistic alterations throughout the AD continuum. Large-scale genome-wide association studies point out several genetic variants—TREM2, CD33, PILRA, CR1, MS4A, CLU, ABCA...
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Frontiers Media S.A.
2020-03-01
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Online Access: | https://www.frontiersin.org/article/10.3389/fimmu.2020.00456/full |
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language |
English |
format |
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author |
Harald Hampel Filippo Caraci Filippo Caraci A. Claudio Cuello A. Claudio Cuello A. Claudio Cuello A. Claudio Cuello Giuseppe Caruso Robert Nisticò Robert Nisticò Massimo Corbo Filippo Baldacci Filippo Baldacci Filippo Baldacci Filippo Baldacci Nicola Toschi Nicola Toschi Nicola Toschi Francesco Garaci Francesco Garaci Patrizia A. Chiesa Patrizia A. Chiesa Patrizia A. Chiesa Steven R. Verdooner Leyla Akman-Anderson Félix Hernández Félix Hernández Jesús Ávila Jesús Ávila Enzo Emanuele Pedro L. Valenzuela Alejandro Lucía Alejandro Lucía Alejandro Lucía Mark Watling Bruno P. Imbimbo Andrea Vergallo Simone Lista Simone Lista Simone Lista |
spellingShingle |
Harald Hampel Filippo Caraci Filippo Caraci A. Claudio Cuello A. Claudio Cuello A. Claudio Cuello A. Claudio Cuello Giuseppe Caruso Robert Nisticò Robert Nisticò Massimo Corbo Filippo Baldacci Filippo Baldacci Filippo Baldacci Filippo Baldacci Nicola Toschi Nicola Toschi Nicola Toschi Francesco Garaci Francesco Garaci Patrizia A. Chiesa Patrizia A. Chiesa Patrizia A. Chiesa Steven R. Verdooner Leyla Akman-Anderson Félix Hernández Félix Hernández Jesús Ávila Jesús Ávila Enzo Emanuele Pedro L. Valenzuela Alejandro Lucía Alejandro Lucía Alejandro Lucía Mark Watling Bruno P. Imbimbo Andrea Vergallo Simone Lista Simone Lista Simone Lista A Path Toward Precision Medicine for Neuroinflammatory Mechanisms in Alzheimer's Disease Frontiers in Immunology Alzheimer's disease neuroinflammation microglia neuroinflammatory pathways biomarkers anti-inflammatory therapy |
author_facet |
Harald Hampel Filippo Caraci Filippo Caraci A. Claudio Cuello A. Claudio Cuello A. Claudio Cuello A. Claudio Cuello Giuseppe Caruso Robert Nisticò Robert Nisticò Massimo Corbo Filippo Baldacci Filippo Baldacci Filippo Baldacci Filippo Baldacci Nicola Toschi Nicola Toschi Nicola Toschi Francesco Garaci Francesco Garaci Patrizia A. Chiesa Patrizia A. Chiesa Patrizia A. Chiesa Steven R. Verdooner Leyla Akman-Anderson Félix Hernández Félix Hernández Jesús Ávila Jesús Ávila Enzo Emanuele Pedro L. Valenzuela Alejandro Lucía Alejandro Lucía Alejandro Lucía Mark Watling Bruno P. Imbimbo Andrea Vergallo Simone Lista Simone Lista Simone Lista |
author_sort |
Harald Hampel |
title |
A Path Toward Precision Medicine for Neuroinflammatory Mechanisms in Alzheimer's Disease |
title_short |
A Path Toward Precision Medicine for Neuroinflammatory Mechanisms in Alzheimer's Disease |
title_full |
A Path Toward Precision Medicine for Neuroinflammatory Mechanisms in Alzheimer's Disease |
title_fullStr |
A Path Toward Precision Medicine for Neuroinflammatory Mechanisms in Alzheimer's Disease |
title_full_unstemmed |
A Path Toward Precision Medicine for Neuroinflammatory Mechanisms in Alzheimer's Disease |
title_sort |
path toward precision medicine for neuroinflammatory mechanisms in alzheimer's disease |
publisher |
Frontiers Media S.A. |
series |
Frontiers in Immunology |
issn |
1664-3224 |
publishDate |
2020-03-01 |
description |
Neuroinflammation commences decades before Alzheimer's disease (AD) clinical onset and represents one of the earliest pathomechanistic alterations throughout the AD continuum. Large-scale genome-wide association studies point out several genetic variants—TREM2, CD33, PILRA, CR1, MS4A, CLU, ABCA7, EPHA1, and HLA-DRB5-HLA-DRB1—potentially linked to neuroinflammation. Most of these genes are involved in proinflammatory intracellular signaling, cytokines/interleukins/cell turnover, synaptic activity, lipid metabolism, and vesicle trafficking. Proteomic studies indicate that a plethora of interconnected aberrant molecular pathways, set off and perpetuated by TNF-α, TGF-β, IL-1β, and the receptor protein TREM2, are involved in neuroinflammation. Microglia and astrocytes are key cellular drivers and regulators of neuroinflammation. Under physiological conditions, they are important for neurotransmission and synaptic homeostasis. In AD, there is a turning point throughout its pathophysiological evolution where glial cells sustain an overexpressed inflammatory response that synergizes with amyloid-β and tau accumulation, and drives synaptotoxicity and neurodegeneration in a self-reinforcing manner. Despite a strong therapeutic rationale, previous clinical trials investigating compounds with anti-inflammatory properties, including non-steroidal anti-inflammatory drugs (NSAIDs), did not achieve primary efficacy endpoints. It is conceivable that study design issues, including the lack of diagnostic accuracy and biomarkers for target population identification and proof of mechanism, may partially explain the negative outcomes. However, a recent meta-analysis indicates a potential biological effect of NSAIDs. In this regard, candidate fluid biomarkers of neuroinflammation are under analytical/clinical validation, i.e., TREM2, IL-1β, MCP-1, IL-6, TNF-α receptor complexes, TGF-β, and YKL-40. PET radio-ligands are investigated to accomplish in vivo and longitudinal regional exploration of neuroinflammation. Biomarkers tracking different molecular pathways (body fluid matrixes) along with brain neuroinflammatory endophenotypes (neuroimaging markers), can untangle temporal–spatial dynamics between neuroinflammation and other AD pathophysiological mechanisms. Robust biomarker–drug codevelopment pipelines are expected to enrich large-scale clinical trials testing new-generation compounds active, directly or indirectly, on neuroinflammatory targets and displaying putative disease-modifying effects: novel NSAIDs, AL002 (anti-TREM2 antibody), anti-Aβ protofibrils (BAN2401), and AL003 (anti-CD33 antibody). As a next step, taking advantage of breakthrough and multimodal techniques coupled with a systems biology approach is the path to pursue for developing individualized therapeutic strategies targeting neuroinflammation under the framework of precision medicine. |
topic |
Alzheimer's disease neuroinflammation microglia neuroinflammatory pathways biomarkers anti-inflammatory therapy |
url |
https://www.frontiersin.org/article/10.3389/fimmu.2020.00456/full |
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doaj-d53ee7186b6d45b1a92b5fefb91691d82020-11-25T03:15:39ZengFrontiers Media S.A.Frontiers in Immunology1664-32242020-03-011110.3389/fimmu.2020.00456509494A Path Toward Precision Medicine for Neuroinflammatory Mechanisms in Alzheimer's DiseaseHarald Hampel0Filippo Caraci1Filippo Caraci2A. Claudio Cuello3A. Claudio Cuello4A. Claudio Cuello5A. Claudio Cuello6Giuseppe Caruso7Robert Nisticò8Robert Nisticò9Massimo Corbo10Filippo Baldacci11Filippo Baldacci12Filippo Baldacci13Filippo Baldacci14Nicola Toschi15Nicola Toschi16Nicola Toschi17Francesco Garaci18Francesco Garaci19Patrizia A. Chiesa20Patrizia A. Chiesa21Patrizia A. Chiesa22Steven R. Verdooner23Leyla Akman-Anderson24Félix Hernández25Félix Hernández26Jesús Ávila27Jesús Ávila28Enzo Emanuele29Pedro L. Valenzuela30Alejandro Lucía31Alejandro Lucía32Alejandro Lucía33Mark Watling34Bruno P. Imbimbo35Andrea Vergallo36Simone Lista37Simone Lista38Simone Lista39Sorbonne University, GRC no. 21, Alzheimer Precision Medicine (APM), AP-HP, Pitié-Salpêtrière Hospital, Boulevard de l'hôpital, Paris, FranceDepartment of Drug Sciences, University of Catania, Catania, ItalyOasi Research Institute—IRCCS, Troina, ItalyDepartment of Neurology and Neurosurgery, McGill University, Montreal, QC, CanadaDepartment of Anatomy and Cell Biology, McGill University, Montreal, QC, CanadaDepartment of Pharmacology and Therapeutics, McGill University, Montreal, QC, CanadaDepartment of Pharmacology, University of Oxford, Oxford, United KingdomOasi Research Institute—IRCCS, Troina, ItalyLaboratory of Neuropharmacology, EBRI Rita Levi-Montalcini Foundation, Rome, ItalySchool of Pharmacy, Department of Biology, University of Rome Tor Vergata, Rome, Italy0Department of Neurorehabilitation Sciences, Casa Cura Policlinico, Milan, ItalySorbonne University, GRC no. 21, Alzheimer Precision Medicine (APM), AP-HP, Pitié-Salpêtrière Hospital, Boulevard de l'hôpital, Paris, France1Brain & Spine Institute (ICM), INSERM U 1127, CNRS UMR 7225, Boulevard de l'hôpital, Paris, France2Institute of Memory and Alzheimer's Disease (IM2A), Department of Neurology, Pitié-Salpêtrière Hospital, AP-HP, Paris, France3Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy4Department of Biomedicine and Prevention, University of Rome “Tor Vergata”, Rome, Italy5Department of Radiology, “Athinoula A. Martinos” Center for Biomedical Imaging, Boston, MA, United States6Harvard Medical School, Boston, MA, United States4Department of Biomedicine and Prevention, University of Rome “Tor Vergata”, Rome, Italy7Casa di Cura “San Raffaele Cassino”, Cassino, ItalySorbonne University, GRC no. 21, Alzheimer Precision Medicine (APM), AP-HP, Pitié-Salpêtrière Hospital, Boulevard de l'hôpital, Paris, France1Brain & Spine Institute (ICM), INSERM U 1127, CNRS UMR 7225, Boulevard de l'hôpital, Paris, France2Institute of Memory and Alzheimer's Disease (IM2A), Department of Neurology, Pitié-Salpêtrière Hospital, AP-HP, Paris, France8NeuroVision Imaging, Inc., Sacramento, CA, United States8NeuroVision Imaging, Inc., Sacramento, CA, United States9Centro de Biología Molecular Severo Ochoa (CSIC-UAM), Madrid, Spain0Network Center for Biomedical Research in Neurodegenerative Diseases (CIBERNED), Madrid, Spain9Centro de Biología Molecular Severo Ochoa (CSIC-UAM), Madrid, Spain0Network Center for Biomedical Research in Neurodegenerative Diseases (CIBERNED), Madrid, Spain12E Science, Robbio, Italy2Systems Biology Department, University of Alcalá, Madrid, Spain3Faculty of Sport Sciences, Universidad Europea de Madrid, Madrid, Spain4Research Institute of the Hospital 12 de Octubre (“imas”), Madrid, Spain5Centro de Investigación Biomédica en Red Fragilidad y Envejecimiento Saludable (CIBERFES), Madrid, Spain6TranScrip Partners, Reading, United Kingdom7Research & Development Department, Chiesi Farmaceutici, Parma, ItalySorbonne University, GRC no. 21, Alzheimer Precision Medicine (APM), AP-HP, Pitié-Salpêtrière Hospital, Boulevard de l'hôpital, Paris, FranceSorbonne University, GRC no. 21, Alzheimer Precision Medicine (APM), AP-HP, Pitié-Salpêtrière Hospital, Boulevard de l'hôpital, Paris, France1Brain & Spine Institute (ICM), INSERM U 1127, CNRS UMR 7225, Boulevard de l'hôpital, Paris, France2Institute of Memory and Alzheimer's Disease (IM2A), Department of Neurology, Pitié-Salpêtrière Hospital, AP-HP, Paris, FranceNeuroinflammation commences decades before Alzheimer's disease (AD) clinical onset and represents one of the earliest pathomechanistic alterations throughout the AD continuum. Large-scale genome-wide association studies point out several genetic variants—TREM2, CD33, PILRA, CR1, MS4A, CLU, ABCA7, EPHA1, and HLA-DRB5-HLA-DRB1—potentially linked to neuroinflammation. Most of these genes are involved in proinflammatory intracellular signaling, cytokines/interleukins/cell turnover, synaptic activity, lipid metabolism, and vesicle trafficking. Proteomic studies indicate that a plethora of interconnected aberrant molecular pathways, set off and perpetuated by TNF-α, TGF-β, IL-1β, and the receptor protein TREM2, are involved in neuroinflammation. Microglia and astrocytes are key cellular drivers and regulators of neuroinflammation. Under physiological conditions, they are important for neurotransmission and synaptic homeostasis. In AD, there is a turning point throughout its pathophysiological evolution where glial cells sustain an overexpressed inflammatory response that synergizes with amyloid-β and tau accumulation, and drives synaptotoxicity and neurodegeneration in a self-reinforcing manner. Despite a strong therapeutic rationale, previous clinical trials investigating compounds with anti-inflammatory properties, including non-steroidal anti-inflammatory drugs (NSAIDs), did not achieve primary efficacy endpoints. It is conceivable that study design issues, including the lack of diagnostic accuracy and biomarkers for target population identification and proof of mechanism, may partially explain the negative outcomes. However, a recent meta-analysis indicates a potential biological effect of NSAIDs. In this regard, candidate fluid biomarkers of neuroinflammation are under analytical/clinical validation, i.e., TREM2, IL-1β, MCP-1, IL-6, TNF-α receptor complexes, TGF-β, and YKL-40. PET radio-ligands are investigated to accomplish in vivo and longitudinal regional exploration of neuroinflammation. Biomarkers tracking different molecular pathways (body fluid matrixes) along with brain neuroinflammatory endophenotypes (neuroimaging markers), can untangle temporal–spatial dynamics between neuroinflammation and other AD pathophysiological mechanisms. Robust biomarker–drug codevelopment pipelines are expected to enrich large-scale clinical trials testing new-generation compounds active, directly or indirectly, on neuroinflammatory targets and displaying putative disease-modifying effects: novel NSAIDs, AL002 (anti-TREM2 antibody), anti-Aβ protofibrils (BAN2401), and AL003 (anti-CD33 antibody). As a next step, taking advantage of breakthrough and multimodal techniques coupled with a systems biology approach is the path to pursue for developing individualized therapeutic strategies targeting neuroinflammation under the framework of precision medicine.https://www.frontiersin.org/article/10.3389/fimmu.2020.00456/fullAlzheimer's diseaseneuroinflammationmicroglianeuroinflammatory pathwaysbiomarkersanti-inflammatory therapy |