Inflammation promotes synucleinopathy propagation

Abstract

The clinical progression of neurodegenerative diseases correlates with the spread of proteinopathy in the brain. The current understanding of the mechanism of proteinopathy spread is far from complete. Here, we propose that inflammation is fundamental to proteinopathy spread. A sequence variant of α-synuclein (V40G) was much less capable of fibril formation than wild-type α-synuclein (WT-syn) and, when mixed with WT-syn, interfered with its fibrillation. However, when V40G was injected intracerebrally into mice, it induced aggregate spreading even more effectively than WT-syn. Aggregate spreading was preceded by sustained microgliosis and inflammatory responses, which were more robust with V40G than with WT-syn. Oral administration of an anti-inflammatory agent suppressed aggregate spreading, inflammation, and behavioral deficits in mice. Furthermore, exposure of cells to inflammatory cytokines increased the cell-to-cell propagation of α-synuclein. These results suggest that the inflammatory microenvironment is the major driver of the spread of synucleinopathy in the brain.

Alpha Synuclein: Neurodegeneration and Inflammation

“…It is important to stress that in these experimental studies, α-Syn transmission and deposition were constantly associated with inflammation induced by α-Syn, and in a vicious circle, inflammation promoted the propagation of α-Syn pathology [ 156 , 157 , 158 ], and intestinal inflammation increased the cerebral α-Syn accumulation [ 159 ].…”

Aggregation‐prone peptides from within a non‐self‐protein homoaggregate are preferred for MHC association: Historical overview

“…49,50 Finally, various brain diseases are associated with intracellular aggregates and an autoimmune aetiology is increasingly recognized. 51,52 That T lymphocytes recognize MHC-displayed peptides from intracellular proteins was discovered in APC studies arising from early work in the Askonas laboratory. 30,38 This led to the postulates that, to avoid autoimmune attack, there might be intracellular mechanisms for distinguishing foreign from self-peptides (e.g.…”

“…This phase‐separating property can be conferred on normal serum by slight concentration (removal of water) or heating to produce albumin aggregates 49,50 . Finally, various brain diseases are associated with intracellular aggregates and an autoimmune aetiology is increasingly recognized 51,52 …”

Targeting Neuroinflammation by Pharmacologic Downregulation of Inflammatory Pathways Is Neuroprotective in Protein Misfolding Disorders

“…These reactive astrocytes are directly toxic to neurons and endothelial cells during prion disease. , Many recent studies, including human patient, in vitro, and in vivo animal models, have pointed to the assembly of the NLRP3 inflammasome in microglia and astrocytes as a significant contributor to inflammatory-related amplification of misfolded proteins in neurodegenerative diseases. − Formation of the NLRP3 inflammasome is a critical step for the activation of pro-inflammatory cytokines and perpetuation of the immune response through microglial pyroptosis. , Pro-caspase-1 is activated by proximity-induced autocatalytic activation upon recruitment to the NLRP3 inflammasome. Active caspase-1 cleaves pro-IL-1β and pro-IL-18 into their mature and biologically active forms, cytokines IL-1β and IL-18. , In mouse models of APP/PS1 mutation and a tauopathy, NLRP3 inflammasome assembly has been identified as a significant contributor to inflammatory-related amplification of Aβ plaques and neurofibrillary tangles. , Similarly, the NLRP3 inflammasome promotes α-Syn production in mouse models of PD. , Activation of NF-kB in prion disease augments neuronal death by increasing the expression of pro-apoptotic genes and triggering the release of cytochrome C, resulting in mitochondrial dysfunction and endoplasmic reticulum stress . Additionally, the upregulation of inflammatory cytokines IL-1β and tumor necrosis factor (TNF), formerly known as tumor necrosis factor α (TNFα), at sites of synaptic damage triggers the production of reactive oxygen species including hydrogen peroxide and nitric oxide, leading to excitotoxicity and neuronal death. − Beyond induction of inflammation and propagation of misfolded proteins, it has been proposed that activation of the NLRP3 inflammasome during neurodegenerative diseases inhibits microglial autophagy, dampening the identification and degradation of misfolded protein aggregates in AD, PD, and prion disease. − …”