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- , and -potentially linked to neuroinfla...
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Published in | Frontiers in immunology Vol. 11; p. 456 |
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Main Authors | , , , , , , , , , , , , , , , , , , , , |
Format | Journal Article |
Language | English |
Published |
Switzerland
Frontiers
31.03.2020
Frontiers Media S.A |
Subjects | |
Online Access | Get full text |
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Summary: | 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-
, and
-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
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. |
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Bibliography: | ObjectType-Article-2 SourceType-Scholarly Journals-1 ObjectType-Feature-3 content type line 23 ObjectType-Review-1 PMCID: PMC7137904 Edited by: Sally Ann Frautschy, University of California, Los Angeles, United States This article was submitted to Multiple Sclerosis and Neuroimmunology, a section of the journal Frontiers in Immunology These authors have contributed equally to this work and share senior authorship Reviewed by: Maria Grazia Cifone, University of L'Aquila, Italy; Maria F. Cano-Abad, Autonomous University of Madrid, Spain |
ISSN: | 1664-3224 1664-3224 |
DOI: | 10.3389/fimmu.2020.00456 |