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Microglial Activation and Priming in Alzheimer’s Disease: State of the Art and Future Perspectives

Alzheimer’s Disease (AD) is the most common cause of dementia, having a remarkable social and healthcare burden worldwide. Amyloid β (Aβ) and protein Tau aggregates are disease hallmarks and key players in AD pathogenesis. However, it has been hypothesized that microglia can contribute to AD pathoph...

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Autores principales: Bivona, Giulia, Iemmolo, Matilda, Agnello, Luisa, Lo Sasso, Bruna, Gambino, Caterina Maria, Giglio, Rosaria Vincenza, Scazzone, Concetta, Ghersi, Giulio, Ciaccio, Marcello
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9820926/
https://www.ncbi.nlm.nih.gov/pubmed/36614325
http://dx.doi.org/10.3390/ijms24010884
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author Bivona, Giulia
Iemmolo, Matilda
Agnello, Luisa
Lo Sasso, Bruna
Gambino, Caterina Maria
Giglio, Rosaria Vincenza
Scazzone, Concetta
Ghersi, Giulio
Ciaccio, Marcello
author_facet Bivona, Giulia
Iemmolo, Matilda
Agnello, Luisa
Lo Sasso, Bruna
Gambino, Caterina Maria
Giglio, Rosaria Vincenza
Scazzone, Concetta
Ghersi, Giulio
Ciaccio, Marcello
author_sort Bivona, Giulia
collection PubMed
description Alzheimer’s Disease (AD) is the most common cause of dementia, having a remarkable social and healthcare burden worldwide. Amyloid β (Aβ) and protein Tau aggregates are disease hallmarks and key players in AD pathogenesis. However, it has been hypothesized that microglia can contribute to AD pathophysiology, as well. Microglia are CNS-resident immune cells belonging to the myeloid lineage of the innate arm of immunity. Under physiological conditions, microglia are in constant motion in order to carry on their housekeeping function, and they maintain an anti-inflammatory, quiescent state, with low expression of cytokines and no phagocytic activity. Upon various stimuli (debris, ATP, misfolded proteins, aggregates and pathogens), microglia acquire a phagocytic function and overexpress cytokine gene modules. This process is generally regarded as microglia activation and implies that the production of pro-inflammatory cytokines is counterbalanced by the synthesis and the release of anti-inflammatory molecules. This mechanism avoids excessive inflammatory response and inappropriate microglial activation, which causes tissue damage and brain homeostasis impairment. Once the pathogenic stimulus has been cleared, activated microglia return to the naïve, anti-inflammatory state. Upon repeated stimuli (as in the case of Aβ deposition in the early stage of AD), activated microglia shift toward a less protective, neurotoxic phenotype, known as “primed” microglia. The main characteristic of primed microglia is their lower capability to turn back toward the naïve, anti-inflammatory state, which makes these cells prone to chronic activation and favours chronic inflammation in the brain. Primed microglia have impaired defence capacity against injury and detrimental effects on the brain microenvironment. Additionally, priming has been associated with AD onset and progression and can represent a promising target for AD treatment strategies. Many factors (genetics, environmental factors, baseline inflammatory status of microglia, ageing) generate an aberrantly activated phenotype that undergoes priming easier and earlier than normally activated microglia do. Novel, promising targets for therapeutic strategies for AD have been sought in the field of microglia activation and, importantly, among those factors influencing the baseline status of these cells. The CX3CL1 pathway could be a valuable target treatment approach in AD, although preliminary findings from the studies in this field are controversial. The current review aims to summarize state of the art on the role of microglia dysfunction in AD pathogenesis and proposes biochemical pathways with possible targets for AD treatment.
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spelling pubmed-98209262023-01-07 Microglial Activation and Priming in Alzheimer’s Disease: State of the Art and Future Perspectives Bivona, Giulia Iemmolo, Matilda Agnello, Luisa Lo Sasso, Bruna Gambino, Caterina Maria Giglio, Rosaria Vincenza Scazzone, Concetta Ghersi, Giulio Ciaccio, Marcello Int J Mol Sci Review Alzheimer’s Disease (AD) is the most common cause of dementia, having a remarkable social and healthcare burden worldwide. Amyloid β (Aβ) and protein Tau aggregates are disease hallmarks and key players in AD pathogenesis. However, it has been hypothesized that microglia can contribute to AD pathophysiology, as well. Microglia are CNS-resident immune cells belonging to the myeloid lineage of the innate arm of immunity. Under physiological conditions, microglia are in constant motion in order to carry on their housekeeping function, and they maintain an anti-inflammatory, quiescent state, with low expression of cytokines and no phagocytic activity. Upon various stimuli (debris, ATP, misfolded proteins, aggregates and pathogens), microglia acquire a phagocytic function and overexpress cytokine gene modules. This process is generally regarded as microglia activation and implies that the production of pro-inflammatory cytokines is counterbalanced by the synthesis and the release of anti-inflammatory molecules. This mechanism avoids excessive inflammatory response and inappropriate microglial activation, which causes tissue damage and brain homeostasis impairment. Once the pathogenic stimulus has been cleared, activated microglia return to the naïve, anti-inflammatory state. Upon repeated stimuli (as in the case of Aβ deposition in the early stage of AD), activated microglia shift toward a less protective, neurotoxic phenotype, known as “primed” microglia. The main characteristic of primed microglia is their lower capability to turn back toward the naïve, anti-inflammatory state, which makes these cells prone to chronic activation and favours chronic inflammation in the brain. Primed microglia have impaired defence capacity against injury and detrimental effects on the brain microenvironment. Additionally, priming has been associated with AD onset and progression and can represent a promising target for AD treatment strategies. Many factors (genetics, environmental factors, baseline inflammatory status of microglia, ageing) generate an aberrantly activated phenotype that undergoes priming easier and earlier than normally activated microglia do. Novel, promising targets for therapeutic strategies for AD have been sought in the field of microglia activation and, importantly, among those factors influencing the baseline status of these cells. The CX3CL1 pathway could be a valuable target treatment approach in AD, although preliminary findings from the studies in this field are controversial. The current review aims to summarize state of the art on the role of microglia dysfunction in AD pathogenesis and proposes biochemical pathways with possible targets for AD treatment. MDPI 2023-01-03 /pmc/articles/PMC9820926/ /pubmed/36614325 http://dx.doi.org/10.3390/ijms24010884 Text en © 2023 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
spellingShingle Review
Bivona, Giulia
Iemmolo, Matilda
Agnello, Luisa
Lo Sasso, Bruna
Gambino, Caterina Maria
Giglio, Rosaria Vincenza
Scazzone, Concetta
Ghersi, Giulio
Ciaccio, Marcello
Microglial Activation and Priming in Alzheimer’s Disease: State of the Art and Future Perspectives
title Microglial Activation and Priming in Alzheimer’s Disease: State of the Art and Future Perspectives
title_full Microglial Activation and Priming in Alzheimer’s Disease: State of the Art and Future Perspectives
title_fullStr Microglial Activation and Priming in Alzheimer’s Disease: State of the Art and Future Perspectives
title_full_unstemmed Microglial Activation and Priming in Alzheimer’s Disease: State of the Art and Future Perspectives
title_short Microglial Activation and Priming in Alzheimer’s Disease: State of the Art and Future Perspectives
title_sort microglial activation and priming in alzheimer’s disease: state of the art and future perspectives
topic Review
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9820926/
https://www.ncbi.nlm.nih.gov/pubmed/36614325
http://dx.doi.org/10.3390/ijms24010884
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