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

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.

The Pathogenesis of Parkinson's Disease: A Complex Interplay Between Astrocytes, Microglia, and T Lymphocytes?

“…Since Iba1 immunoreactivity was co-localised with TLR2 it is thought that this receptor may play a key role in microgliosis ( 83 ). This localised microgliosis is also present in the MPTP mouse model of PD ( 84 ), the A53T α-syn transgenic mouse model of PD following administration of LPS ( 85 ) and the L-dopa-induced dyskinesia rat model of PD ( 86 ). Blocking microglial activation with a combination of matrix metalloproteinase inhibitor 1-DNJ plus ibuprofen is protective against dopamine neuronal loss ( 87 ) suggesting that microglia are key contributors to PD pathology.…”

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

“…100 This finding suggests that inflammation, particularly IL-1, plays a role in mediating the initiation and propagation of αSyn pathology from the OB. 100 In relation to systemic inflammation, La Vitola et al 101 developed a PD mouse model through systemic administration of LPS followed by intracerebroventricular injection of an αSyn oligo-mer as well as an αSyn-overexpression transgenic mouse administered LPS. The authors demonstrated that peripherally induced neuroinflammation influences the action of αSyn oligomers to potentiate a detrimental effect.…”

“…The authors demonstrated that peripherally induced neuroinflammation influences the action of αSyn oligomers to potentiate a detrimental effect. 101 The influence of the adaptive immune system on αSyn has also been explored. 102 By crossing human αSyn-overexpressing transgenic mice and lymphocytelacking mice, Sommer et al 102 determined that the presence of T lymphocytes modulated toward a proinflammatory M1 phenotype was associated with an increased number of αSyn aggregates in the SN and striatum.…”

Green Tea Polyphenol Epigallocatechin-Gallate in Amyloid Aggregation and Neurodegenerative Diseases

“…Amyloid diseases are multifactorial diseases since in addition to the damage caused by protein deposition per se and oligomer-related injuries, inflammation also plays an important role in disease progression and prognosis ( Azevedo et al, 2019 ; La Vitola et al, 2021 ). Promising compounds must cross the blood–brain barrier (BBB) when neurodegenerative disorders are considered.…”