Inflammatory Animal Models of Parkinson’s Disease

García-Revilla, Juan; Herrera, Antonio J.; Pablos, Rocío M. de; Venero, José L.

doi:10.3233/jpd-213138

Cited by 16 publications

(12 citation statements)

References 173 publications

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“…In our model, LPS peripheral treatment induced glial reactivity per se; the synergic effect can be restricted to the CNS. As reported by Garcia-Revilla et al (2022) [ 183 ] in several experimental models including rotenone and 6OHDA injections, the influence of general inflammation on central neurotoxic activity is well established. The different reactivity of astrocytes and microglia is important evidence that needs to be considered in the PD pathogenesis; the astrocyte dysfunction might contribute to the neurodegenerative process in synucleinopathies [ 184 , 185 ].…”

Section: Alpha-synuclein and Inflammationmentioning

confidence: 76%

Alpha Synuclein: Neurodegeneration and Inflammation

Forloni

2023

IJMS

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Alpha-Synuclein (α-Syn) is one of the most important molecules involved in the pathogenesis of Parkinson’s disease and related disorders, synucleinopathies, but also in several other neurodegenerative disorders with a more elusive role. This review analyzes the activities of α-Syn, in different conformational states, monomeric, oligomeric and fibrils, in relation to neuronal dysfunction. The neuronal damage induced by α-Syn in various conformers will be analyzed in relation to its capacity to spread the intracellular aggregation seeds with a prion-like mechanism. In view of the prominent role of inflammation in virtually all neurodegenerative disorders, the activity of α-Syn will also be illustrated considering its influence on glial reactivity. We and others have described the interaction between general inflammation and cerebral dysfunctional activity of α-Syn. Differences in microglia and astrocyte activation have also been observed when in vivo the presence of α-Syn oligomers has been combined with a lasting peripheral inflammatory effect. The reactivity of microglia was amplified, while astrocytes were damaged by the double stimulus, opening new perspectives for the control of inflammation in synucleinopathies. Starting from our studies in experimental models, we extended the perspective to find useful pointers to orient future research and potential therapeutic strategies in neurodegenerative disorders.

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Section: Alpha-synuclein and Inflammationmentioning

confidence: 76%

Alpha Synuclein: Neurodegeneration and Inflammation

Forloni

2023

IJMS

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“…After neuron death and collapse, neuromelanin is released into the extraneuronal space and slowly phagocytosed by microglial cells. The degradation of neuromelanin can not only activate microglial cells leading to the release of inflammatory and toxic mediators including TNF‐α and IL‐6 but also discharge toxic compounds and excess iron ions 192 . In addition, IL‐6, via its trans‐signaling pathway, induces changes in the neuronal iron transcriptome that promote ferrous iron uptake and decrease cellular iron export via the cellular iron sequestration response 193 .…”

Section: Iron Metabolism In Brain Diseasesmentioning

confidence: 99%

Iron homeostasis imbalance and ferroptosis in brain diseases

Long

Zhu

Wei

et al. 2023

MedComm

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Brain iron homeostasis is maintained through the normal function of blood–brain barrier and iron regulation at the systemic and cellular levels, which is fundamental to normal brain function. Excess iron can catalyze the generation of free radicals through Fenton reactions due to its dual redox state, thus causing oxidative stress. Numerous evidence has indicated brain diseases, especially stroke and neurodegenerative diseases, are closely related to the mechanism of iron homeostasis imbalance in the brain. For one thing, brain diseases promote brain iron accumulation. For another, iron accumulation amplifies damage to the nervous system and exacerbates patients’ outcomes. In addition, iron accumulation triggers ferroptosis, a newly discovered iron‐dependent type of programmed cell death, which is closely related to neurodegeneration and has received wide attention in recent years. In this context, we outline the mechanism of a normal brain iron metabolism and focus on the current mechanism of the iron homeostasis imbalance in stroke, Alzheimer's disease, and Parkinson's disease. Meanwhile, we also discuss the mechanism of ferroptosis and simultaneously enumerate the newly discovered drugs for iron chelators and ferroptosis inhibitors.

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“…Neuroinflammatory changes within the brain have been identified as a central event in PD [20]. Lipopolysaccharide (LPS) is a component of the outer membrane of gram‐negative bacteria, and its presence can induce inflammation in host organisms [21]. Recent studies have shown that exposure to LPS can exacerbate the formation of amyloid fibrils of aSyn, in which the endotoxin can directly alter the conformation of the protein; as a result, the protein becomes more prone to fibrillation.…”

Section: Introductionmentioning

confidence: 99%

Fibrillation of α‐synuclein triggered by bacterial endotoxin and lipid vesicles is modulated by N‐terminal acetylation and familial Parkinson's disease mutations

Monteiro Neto,

Lima,

Follmer

2023

The FEBS Journal

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It has been hypothesized that ‐‐Parkinson's disease (PD) may be initiated in the gastrointestinal tract, before manifesting in the central nervous system. In this respect, it was demonstrated that lipopolysaccharide (LPS), an endotoxin from gram‐negative bacteria, accelerates the in vitro formation of α‐synuclein (aSyn) fibrils, whose intracellular deposits is a histological hallmark of the degeneration of dopaminergic neurons in PD. Herein, N‐terminal acetylation and missense mutations of aSyn (A30P, A53T, E46K, H50Q and G51D) linked to rare, early‐onset forms of familial PD were investigated regarding their effect on aSyn aggregation stimulated by either LPS or small unilamellar lipid vesicles (SUVs). Our findings indicated that LPS as well as SUVs induce the fibrillation of N‐terminally acetylated wild‐type aSyn (Ac‐aSyn‐WT) more remarkably than the non‐acetylated protein, while the LPS‐free protein alone did not undergo fibrillation under our assay conditions. In addition, with the exception of A30P, PD mutations increased the fibrillation of Ac‐aSyn in the presence of LPS compared with Ac‐aSyn‐WT. The most pronounced effect of LPS was noticed for A53T, as observed when either Thioflavin‐T or JC‐1 were used as fluorescent probes for fibrils. Overall, our results suggest for the first time the existence of a synergy between LPS and PD mutations/N‐terminal acetylation toward aSyn fibrillation.

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Inflammatory Animal Models of Parkinson’s Disease

Cited by 16 publications

References 173 publications

Alpha Synuclein: Neurodegeneration and Inflammation

Alpha Synuclein: Neurodegeneration and Inflammation

Iron homeostasis imbalance and ferroptosis in brain diseases

Fibrillation of α‐synuclein triggered by bacterial endotoxin and lipid vesicles is modulated by N‐terminal acetylation and familial Parkinson's disease mutations

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