Intrastriatal injection of preformed alpha-synuclein fibrils alters central and peripheral immune cell profiles in non-transgenic mice

Rachael H Earls,Jae-Kyung Lee,Manuel G Hazim,Kelly B Menees,Jaegwon Chung,Claire-Anne Gutekunst,James Barber

doi:10.1186/s12974-019-1636-8

Rachael H Earls, Jae-Kyung Lee + Show 5 more

Open Access

https://doi.org/10.1186/s12974-019-1636-8

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Abstract

Parkinson’s disease (PD) is characterized by the accumulation of alpha-synuclein (α-syn) inclusions, the major component of Lewy bodies. Extracellular α-syn aggregates act as a damage-associated molecular pattern (DAMP) and the presence of autoantibodies against α-syn species in the cerebrospinal fluid and the serum of PD patients implicate the involvement of innate and adaptive immune responses. In non-transgenic (Tg) mice, intrastriatal injection of preformed fibril (PFF) α-syn results in widespread pathologic α-syn inclusions in the CNS. While the PFF model has been broadly utilized to study the mechanistic relationship between α-syn transmission and other neuropathological phenotypes, the immune phenotypes in this model are not clearly demonstrated. This study aimed to characterize the immune phenotypes during pathologic α-syn propagation by utilizing PFF α-syn–injected non-tg mice. Here, we showed that pathologic α-syn inclusions are prevalent in various brain regions and the gut at 5 months post injection (p.i.), preceding the degeneration of dopaminergic neurons in substantia nigra (SN). We discovered a distinct inflammatory response involving both activation of microglia and astrocytes and infiltration of B, CD4+ T, CD8+ T, and natural killer cells in the brain at 5 months p.i. Moreover, PFF α-syn–injected mice display significant alterations in the frequency and number of leukocyte subsets in the spleen and lymph nodes with minimum alterations in the blood. Our data provide primary evidence that intracerebral-initiated synucleinopathies in non-tg mice alter immune cell profiles both in the CNS and peripheral lymphoid organs. Furthermore, our data provides support for utilizing this mouse model to assess the mechanistic connection between immune responses and synuclein pathology.

Highlights

Parkinson’s disease (PD) is a devastating neurological disorder that affects over half a million people in the USA [1]
In non-Tg mice inoculated with preformed fibril (PFF) α-syn, we showed for the first time that Lewy Body (LB)-like pathology led Peripherally, α-syn aggregates were found within the myenteric plexus of the gut [45]
The meningeal lymphatic system drains directly into the deep cervical lymph nodes [51] and acts as a route for drainage of macromolecules, such as the amyloid-beta (Aβ) protein seen in Alzheimer’s disease (AD) [52], which may attribute to the conventional lymphatic vasculature in the periphery as we observed the changes in peripheral immune phenotypes in our mouse model; (2) Another possible mechanism is the intimate connection of the gut-brain axis

Summary

Introduction

Parkinson’s disease (PD) is a devastating neurological disorder that affects over half a million people in the USA [1]. The preformed fibril (PFF) α-syn model has been utilized as an animal model of PD because it exhibits many clinically relevant hallmarks of PD including dopaminergic cell loss, behavioral deficits, and synucleinopathies [23]. In this model, PFF α-syn acts as seeds for formation of the endogenous α-syn aggregates, which lead to propagation of pathology and subsequent neurodegeneration. While the PFF α-syn model has been widely utilized to explore the mechanistic relationship between α-syn transmission and other neurological phenotypes that are clinically relevant to PD [23], their immune phenotypes during synuclein aggregation and propagation have not been fully characterized. We characterized immune phenotypes in the CNS and the periphery of PFF α-syn–injected nonTg mice

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