Neuroinflammation, immune response and α-synuclein pathology: how animal models are helping us to connect dots

ABSTRACT

Introduction

A key pathological event occurring in Parkinson’s disease (PD) is the transneuronal spreading of alpha-synuclein (α-syn). Other hallmarks of PD include neurodegeneration, glial activation, and immune cell infiltration in susceptible brain regions. Although preclinical models can mimic most of the key characteristics of PD, it is crucial to know the biological bases of individual differences between them when choosing one over another, to ensure proper interpretation of the results and to positively influence the outcome of the experiments.

Areas covered

This review provides an overview of current preclinical models actively used to study the interplay between α-syn pathology, neuroinflammation and immune response in PD but also to explore new potential preclinical models or emerging therapeutic strategies intended to fulfill the unmet medical needs in this disease. Lastly, this review also considers the current state of the ongoing clinical trials of new drugs designed to target these processes and delay the initiation or progression of the disease.

Expert opinion

Anti-inflammatory and immunomodulatory agents have been demonstrated to be very promising candidates for reducing disease progression; however, more efforts are needed to reduce the enormous gap between these and dopaminergic drugs, which have dominated the therapeutic market for the last sixty years.

KEYWORDS:

• Immune cells
• NE3107
• neuroinflammation
• Parkinson’s disease
• Sargramostim

Article highlights

• Transgenic α-synuclein models, recombinant adeno-associated viral vector-α-syn models and animals inoculated with monomers, oligomers and fibrils of α-synuclein are useful animal models to investigate the interplay between neuroinflammation, immune response and α-synuclein in Parkinson’s disease.

• The choice of the correct model is one of the main steps on the way to discovery of new targets, providing a bridge between preclinical studies and more reliable therapeutic candidates.

• Neuroinflammatory mediators and immune cell infiltration boost the effects of α-synuclein in the progression of disease and precede nigrostriatal dopaminergic loss.

• Anti-inflammatory and immunologic/immunosuppressant agents have been demonstrated to be very promising candidates to reduce disease progression, especially at very early stages.

• The early detection of neuroinflammatory and brain immune changes in PD patients and the development of new preclinical models for the discovery of new molecular targets and more reliable therapeutic candidates represent two major challenges to reduce the enormous gap compared with dopaminergic drugs for the treatment of the disease.

This box summarizes key points contained in the article.

Declaration of interest

The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Additional information

Funding

The authors are funded by Ayudas para contratos Juan de la Cierva-Incorporacion (IJC2020-043918-I) of the Ministry of Science and Innovation, the National Research Agency and the European Union NextGenerationEU/PRTR (Recovery, Transformation and Resilience Plan) (awarded to T Balzano). They are also funded by Contratos Miguel Servet (MS19/00200) and Fondo de Investigaciones Sanitarias (PI20/00496) (awarded to J Blesa) as well as Contratos Predoctorales de Formación en Investigación en Salud (FI21/000919) (awarded to N Esteban-Garcia) of the Instituto de Salud Carlos III.