Aims: Parkinson’s disease and related disorders are devastating neurodegenerative pathologies. Since α-synuclein was identified as a main component of Lewy bodies and neurites, efforts have been made to clarify the pathogenic mechanisms of α-synuclein's detrimental effects. α-synuclein oligomers are the most harmful species and may recruit and activate glial cells. Inflammation is emerging as a bridge between genetic susceptibility and environmental factors co-fostering Parkinson’s disease. However, direct evidence linking inflammation to the harmful activities of α-synuclein oligomers or to the Parkinson’s disease behavioural phenotype is lacking. Methods: To clarify whether neuroinflammation influences Parkinson’s disease pathogenesis, we developed: (i) a ‘double-hit’ approach in C57BL/6 naive mice where peripherally administered lipopolysaccharides were followed by intracerebroventricular injection of an inactive oligomer dose; (ii) a transgenic ‘double-hit’ model where lipopolysaccharides were given to A53T α-synuclein transgenic Parkinson’s disease mice. Results: Lipopolysaccharides induced a long-lasting neuroinflammatory response which facilitated the detrimental cognitive activities of oligomers. LPS-activated microglia and astrocytes responded differently to the oligomers with microglia activating further and acquiring a pro-inflammatory M1 phenotype, while astrocytes atrophied. In the transgenic ‘double-hit’ A53T mouse model, lipopolysaccharides aggravated cognitive deficits and increased microgliosis. Again, astrocytes responded differently to the double challenge. These findings indicate that peripherally induced neuroinflammation potentiates the α-synuclein oligomer’s actions and aggravates cognitive deficits in A53T mice. Conclusions: The fine management of both peripheral and central inflammation may offer a promising therapeutic approach to prevent or slow down some behavioural aspects in α-synucleinopathies.

Peripheral inflammation exacerbates α-synuclein toxicity and neuropathology in Parkinson's models / P. La Vitola, C. Balducci, M. Baroni, L. Artioli, G. Santamaria, M. Castiglioni, M. Cerovic, L. Colombo, L. Caldinelli, L. Pollegioni, G. Forloni. - In: NEUROPATHOLOGY AND APPLIED NEUROBIOLOGY. - ISSN 0305-1846. - 47:1(2021 Feb), pp. 43-60.

Peripheral inflammation exacerbates α-synuclein toxicity and neuropathology in Parkinson's models

L. Artioli;
2021

Abstract

Aims: Parkinson’s disease and related disorders are devastating neurodegenerative pathologies. Since α-synuclein was identified as a main component of Lewy bodies and neurites, efforts have been made to clarify the pathogenic mechanisms of α-synuclein's detrimental effects. α-synuclein oligomers are the most harmful species and may recruit and activate glial cells. Inflammation is emerging as a bridge between genetic susceptibility and environmental factors co-fostering Parkinson’s disease. However, direct evidence linking inflammation to the harmful activities of α-synuclein oligomers or to the Parkinson’s disease behavioural phenotype is lacking. Methods: To clarify whether neuroinflammation influences Parkinson’s disease pathogenesis, we developed: (i) a ‘double-hit’ approach in C57BL/6 naive mice where peripherally administered lipopolysaccharides were followed by intracerebroventricular injection of an inactive oligomer dose; (ii) a transgenic ‘double-hit’ model where lipopolysaccharides were given to A53T α-synuclein transgenic Parkinson’s disease mice. Results: Lipopolysaccharides induced a long-lasting neuroinflammatory response which facilitated the detrimental cognitive activities of oligomers. LPS-activated microglia and astrocytes responded differently to the oligomers with microglia activating further and acquiring a pro-inflammatory M1 phenotype, while astrocytes atrophied. In the transgenic ‘double-hit’ A53T mouse model, lipopolysaccharides aggravated cognitive deficits and increased microgliosis. Again, astrocytes responded differently to the double challenge. These findings indicate that peripherally induced neuroinflammation potentiates the α-synuclein oligomer’s actions and aggravates cognitive deficits in A53T mice. Conclusions: The fine management of both peripheral and central inflammation may offer a promising therapeutic approach to prevent or slow down some behavioural aspects in α-synucleinopathies.
neuroinflammation; nonmotor deficits; oligomeropathies; Parkinson’s disease; α-synuclein oligomers
Settore BIO/13 - Biologia Applicata
6-ago-2020
Article (author)
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/2434/825423
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