Inflammatory Animal Models of Parkinson's Disease

Abstract

Accumulating evidence suggests that microglia and peripheral immune cells may play determinant roles in the pathogenesis of Parkinson's disease (PD). Consequently, there is a need to take advantage of immune-related models of PD to study the potential contribution of microglia and peripheral immune cells to the degeneration of the nigrostriatal system and help develop potential therapies for PD. In this review, we have summarised the main PD immune models. From a historical perspective, we highlight first the main features of intranigral injections of different pro-inflammogens, including lipopolysaccharide (LPS), thrombin, neuromelanin, etc. The use of adenoviral vectors to promote microglia-specific overexpression of different molecules in the ventral mesencephalon, including α-synuclein, IL-1β, and TNF, are also presented and briefly discussed. Finally, we summarise different models associated with peripheral inflammation whose contribution to the pathogenesis of neurodegenerative diseases is now an outstanding question. Illustrative examples included systemic LPS administration and dextran sulfate sodium-induced colitis in rodents.

Keywords: Parkinson’s disease; adenovirus; animal models; dextran sulfate sodium; inflammation; lipopolysaccharide; microglia; substantia nigra; thrombin.

Fig. 1

A) Inflammatory models of Parkinson’s disease take advantage of the use of different proinflammatory compounds administered peripherally, intracerebral, or by combining both pathways. B) Whatever compound and route of administration used, homeostatic microglia sense the environment through a set of surface receptors (the pattern recognition receptors, PRRs), including TLR2, TLR4, and RAGE. C) When activated, microglia undergo molecular and morphological changes, becoming reactive microglia. Illustrative examples are the DAM phenotype driven by TREM2 or the proinflammatory phenotype driven by TLR activation. Different microglia phenotypes can coexist under neurodegenerative conditions. Their activation leads to activation of the NF-κB pathway and the transcription of several proinflammatory genes (TNF and IL-6). Assembly of the NLRP3 inflammasome and activation of caspase-1 produce IL-1β and IL-18. Reactive microglia are also a source of ROS and RNS. All these products exert a harmful effect on dopaminergic neurons, which in turn release substances such as ATP, neuromelanin, and different forms of α-syn (either monomers or aggregates) that bind microglial PRRs in a vicious cycle that eventually leads to the death of dopaminergic neurons. Modified from Herrera et al., 2018 [169] using BioRender.