Inflammation in Experimental Models of α<scp>‐Synucleinopathies</scp>

Harms, Ashley S.; Kordower, Jeffrey H.; Sette, Alessandro; Arlehamn, Cecilia S. Lindestam; Sulzer, David; Mach, Robert H.

doi:10.1002/mds.28264

Cited by 26 publications

(29 citation statements)

References 130 publications

(258 reference statements)

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“…It has been proposed that the neuron-microglia interaction may contribute to the neuroinflammation that characterizes PD, where neurons expressing aSyn activate microglia, which in turn secrete inflammatory factors surrounding the diseased neurons, thus forming a vicious cycle [ 456 ] ( Figure 3 ). Likewise, microgliosis has been also reported in MSA, where aSyn is found aggregated mainly within oligodendrocytes [ 426 , 457 , 458 , 459 ]. This hypothesis for neuron-microglia communication in synucleinopathies is further supported by findings demonstrating an altered expression profile of various cytokines in the brains of PD patients [ 460 ].…”

Section: Glia In the Cns: Scavengers Of Extracellular Asynmentioning

confidence: 87%

Neurons and Glia Interplay in α-Synucleinopathies

Mavroeidi

Xilouri

2021

IJMS

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Accumulation of the neuronal presynaptic protein alpha-synuclein within proteinaceous inclusions represents the key histophathological hallmark of a spectrum of neurodegenerative disorders, referred to by the umbrella term a-synucleinopathies. Even though alpha-synuclein is expressed predominantly in neurons, pathological aggregates of the protein are also found in the glial cells of the brain. In Parkinson’s disease and dementia with Lewy bodies, alpha-synuclein accumulates mainly in neurons forming the Lewy bodies and Lewy neurites, whereas in multiple system atrophy, the protein aggregates mostly in the glial cytoplasmic inclusions within oligodendrocytes. In addition, astrogliosis and microgliosis are found in the synucleinopathy brains, whereas both astrocytes and microglia internalize alpha-synuclein and contribute to the spread of pathology. The mechanisms underlying the pathological accumulation of alpha-synuclein in glial cells that under physiological conditions express low to non-detectable levels of the protein are an area of intense research. Undoubtedly, the presence of aggregated alpha-synuclein can disrupt glial function in general and can contribute to neurodegeneration through numerous pathways. Herein, we summarize the current knowledge on the role of alpha-synuclein in both neurons and glia, highlighting the contribution of the neuron-glia connectome in the disease initiation and progression, which may represent potential therapeutic target for a-synucleinopathies.

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Section: Glia In the Cns: Scavengers Of Extracellular Asynmentioning

confidence: 87%

Neurons and Glia Interplay in α-Synucleinopathies

Mavroeidi

Xilouri

2021

IJMS

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“…[36][37][38] In a study using 11 C-DPA713, a significant increase in uptake was shown in the occipital, temporal, and parietal cortex of the brains of PD patients. 36 Significantly higher microglial activation was also shown with 18 F-DPA714 in the midbrain, frontal cortex, and putamen of PD patients relative to controls. 38 In summary, microglial activation has been evidenced in vivo by PET studies in the premotor or clinical stages of PD.…”

Section: In Vivo Evidence Of Inflammation In Pd Patientsmentioning

confidence: 94%

Evidence of Inflammation in Parkinson’s Disease and Its Contribution to Synucleinopathy

Lai

Kim

et al. 2022

JMD

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Accumulation of alpha-synuclein (αSyn) protein in neurons is a renowned pathological hallmark of Parkinson's disease (PD). In addition, accumulating evidence indicates that activated inflammatory responses are involved in the pathogenesis of PD. Thus, achieving a better understanding of the interaction between inflammation and synucleinopathy in relation to the PD process will facilitate the development of promising disease-modifying therapies. In this review, the evidence of inflammation in PD is discussed, and human, animal, and laboratory studies relevant to the relationship between inflammation and αSyn are explored as well as new therapeutic targets associated with this relationship.

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Section: Introductionmentioning

confidence: 99%

“…In addition to αSyn propagation, neuroin ammation has been suggested as one of the main mechanisms contributing to PD pathogenesis 4,5 . Postmortem studies using PD brain reported extensive microgliosis in the brain regions affected by synuclein pathology 4,6 . Besides microglia, astrocytic activation, and increased MHC-II, MHC-I expression as the adaptive immune response has also been reported to contribute to the progression of PD 7,8 .…”

Section: Introductionmentioning

confidence: 99%

“…In another aspect, neuroprotective function of microglia in the αSyn transmission was proposed 9 . Although the precise role of in ammation in this αSyn-associated disease process is not fully understood, in ammation may be not just the result of disease process but the contributor in the progressive nature of synucleinopathy [4][5][6]9,10 . Additionally, microglia and astrocyte may play a different or shared role in the PD pathogenesis.…”

Section: Introductionmentioning

confidence: 99%

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Temporal evolution of inflammation and neurodegeneration with alpha-synuclein propagation in Parkinson’s disease mouse model

Lai

Kim

Nguyen

et al. 2021

Preprint

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Alpha-synuclein (αSyn) propagation has been determined to play a key role in the pathomechanism of Parkinson’s disease (PD), but neurodegeneration and the involvement of inflammation in its pathologic progression are yet to be well understood with regard to temporal relationship. In this study, by means of PD mouse model injected with intrastriatal αSyn preformed fibril (PFF), the temporal evolution of αSyn propagation, inflammation, and neurodegeneration was explored in the perspective of the striatum and the whole brain. In the PFF-injected striatum, inflammatory responses including the microglia and astrocyte were activated at the earliest stage and reduced with time, and the phosphorylated form of αSyn accumulation increased behind it. Thereafter, the degeneration of striatal dopaminergic neurons became significant with the conspicuity of behavior phenotype. Similar pattern of forefront eruption of inflammation and following αSyn propagation was noted in the opposite striatum, which was not injected with PFF. Meanwhile, in analyzing the whole brain, inflammatory responses were determined to have activated at the earliest stage, and the soluble αSyn expression then increased concurrently. Inflammatory response decreased afterward, and the accumulation of the insoluble form of αSyn increased behind it. Our results suggested that the inflammatory response may precede the accumulation of the pathologic form of αSyn; thereafter, the neurodegeneration and motor dysfunction followed αSyn proliferation in PD mouse model. From this model, recognizing the temporal relationship between inflammation, αSyn propagation, and neurodegeneration may be helpful in establishing PD animal model and monitoring the effect of interventional therapy.

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Inflammation in Experimental Models of α‐Synucleinopathies

Cited by 26 publications

References 130 publications

Neurons and Glia Interplay in α-Synucleinopathies

Neurons and Glia Interplay in α-Synucleinopathies

Evidence of Inflammation in Parkinson’s Disease and Its Contribution to Synucleinopathy

Temporal evolution of inflammation and neurodegeneration with alpha-synuclein propagation in Parkinson’s disease mouse model

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