A Path Toward Precision Medicine for Neuroinflammatory Mechanisms in Alzheimer's Disease

Frontiers in Immunology

Steven R. Verdooner²  Massimo Corbo³  Jesús Ávila⁴  Pedro L. Valenzuela⁴  Patrizia A. Chiesa⁶  Filippo Baldacci⁷  Leyla Akman-Anderson⁷  Alejandro Lucía^1,10  Francesco Garaci^1,11  Mark Watling^1,12  Bruno P. Imbimbo^1,13  Nicola Toschi^1,14  Andrea Vergallo^1,16  Félix Hernández^1,19  Enzo Emanuele^2,20  A. Claudio Cuello^2,25  Giuseppe Caruso^2,27  Filippo Caraci^2,27  Robert Nisticò^2,28  Harald Hampel^2,29  Simone Lista^2,29 

[1] Development Department, Chiesi Farmaceutici, Parma, Italy;Spine Institute (ICM), INSERM U 1127, CNRS UMR 7225, Boulevard de l'hôpital, Paris, France;0Department of Neurorehabilitation Sciences, Casa Cura Policlinico, Milan, Italy;0Network Center for Biomedical Research in Neurodegenerative Diseases (CIBERNED), Madrid, Spain;12E Science, Robbio, Italy;;1Brain &2Institute of Memory and Alzheimer's Disease (IM2A), Department of Neurology, Pitié-Salpêtrière Hospital, AP-HP, Paris, France;2Systems Biology Department, University of Alcalá, Madrid, Spain;3Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy;3Faculty of Sport Sciences, Universidad Europea de Madrid, Madrid, Spain;4Department of Biomedicine and Prevention, University of Rome “Tor Vergata”, Rome, Italy;4Research Institute of the Hospital 12 de Octubre (“imas”), Madrid, Spain;5Centro de Investigación Biomédica en Red Fragilidad y Envejecimiento Saludable (CIBERFES), Madrid, Spain;5Department of Radiology, “Athinoula A. Martinos” Center for Biomedical Imaging, Boston, MA, United States;6Harvard Medical School, Boston, MA, United States;6TranScrip Partners, Reading, United Kingdom;7Casa di Cura “San Raffaele Cassino”, Cassino, Italy;;7Research &8NeuroVision Imaging, Inc., Sacramento, CA, United States;9Centro de Biología Molecular Severo Ochoa (CSIC-UAM), Madrid, Spain;Department of Anatomy and Cell Biology, McGill University, Montreal, QC, Canada;Department of Drug Sciences, University of Catania, Catania, Italy;Department of Neurology and Neurosurgery, McGill University, Montreal, QC, Canada;Department of Pharmacology and Therapeutics, McGill University, Montreal, QC, Canada;Department of Pharmacology, University of Oxford, Oxford, United Kingdom;Laboratory of Neuropharmacology, EBRI Rita Levi-Montalcini Foundation, Rome, Italy;Oasi Research Institute—IRCCS, Troina, Italy;School of Pharmacy, Department of Biology, University of Rome Tor Vergata, Rome, Italy;Sorbonne University, GRC no. 21, Alzheimer Precision Medicine (APM), AP-HP, Pitié-Salpêtrière Hospital, Boulevard de l'hôpital, Paris, France;

关键词: Alzheimer's disease;    neuroinflammation;    microglia;    neuroinflammatory pathways;    biomarkers;    anti-inflammatory therapy;   

DOI  :  10.3389/fimmu.2020.00456

来源: DOAJ

【 摘 要 】

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.

【 授权许可】

Unknown