Inflammation Triggers Synaptic Alteration and Degeneration in Experimental Autoimmune Encephalomyelitis

Abstract

Neurodegeneration is the irremediable pathological event occurring during chronic inflammatory diseases of the CNS. Here we show that, in experimental autoimmune encephalomyelitis (EAE), a mouse model of multiple sclerosis, inflammation is capable in enhancing glutamate transmission in the striatum and in promoting synaptic degeneration and dendritic spine loss. These alterations occur early in the disease course, are independent of demyelination, and are strongly associated with massive release of tumor necrosis factor-␣ from activated microglia. CNS invasion by myelin-specific blood-borne immune cells is the triggering event, and the downregulation of the early gene Arc/Arg3.1, leading to the abnormal expression and phosphorylation of AMPA receptors, represents a culminating step in this cascade of neurodegenerative events. Accordingly, EAE-induced synaptopathy subsided during pharmacological blockade of AMPA receptors. Our data establish a link between neuroinflammation and synaptic degeneration and calls for early neuroprotective therapies in chronic inflammatory diseases of the CNS.

Retrograde interferon‐gamma signaling induces major histocompatibility class I expression in human‐induced pluripotent stem cell‐derived neurons

“…Evidence also suggests that MHC I is involved with synaptic pruning during cortical development12, 13, 14, 16, 17, 18, 19, 20, 21 and following injury22, 23, 24, 25 and contributes to neuronal plasticity 16, 17, 26, 27. These findings also suggest that retrogradely induced MHC class I may contribute to the diffuse synaptopathy observed in MS and other neurodegenerative diseases 28, 29, 30, 31, 32, 33, 34, 35. However, whether human neurons and axons respond to inflammatory stress in this way is unknown, and the dearth of methods for efficiently culturing human neurons and isolated axons has prevented robust analysis.…”

“…On the other hand, a pathogenic role for retrograde induction of MHC I by IFN γ in MS is likely to be associated with gray matter pathology that occurs remotely from active demyelinating lesions. Diffuse synapse loss with altered cortical connectivity, as well as diffuse neuron and axon loss, are all commonly found in MS tissue 28, 29, 30, 31, 32, 33, 34, 60, 61, 62, 63 and could be driven by somatic or axonal MHC I expression. For example, neuronal MHC I has an established role in neuronal plasticity16 via mechanisms involving postsynaptic interactions with glutamate receptors and presynaptic interactions with the immunoreceptor tyrosine‐based inhibitory motif‐containing leukocyte immunoglobulin‐like receptor PirB 64.…”

Acid-Sensing Ion Channels Contribute to the Effect of Acidosis on the Function of Dendritic Cells

“…Therefore, DCs are critical for the induction of immune responses triggered by microorganisms, tumors, and autoantigens. Recently, there is increasing evidence to suggest that inflammation plays an important role in various diseases, such as tumors and autoimmune diseases (32)(33)(34)(35). Inflammation is always accompanied by tissue acidification, which means that the microenvironment of pathological sites is acidic compared with normal sites; however, the effect of an acidic microenvironment on the physiological functions of DCs is less well known.…”

Nitric Oxide Induces Pathological Synapse Loss by a Protein Kinase G-, Rho Kinase-Dependent Mechanism Preceded by Myosin Light Chain Phosphorylation

“…Synapse loss, rather than cell death, is the main factor underlying cognitive decline in Alzheimer's disease (AD) (Palop et al, 2006;Small, 2008), Parkinson's disease (PD) (Emre, 2003), Huntington's disease (HD) (Cepeda et al, 2007), multiple sclerosis (MS) (Centonze et al, 2009), and HIV dementia (Kim et al, 2008) in patients and/or in animal models. Synaptic stripping from the motoneuron surface also occurs in the progression of several motoneuron pathologies, such as amyotrophic lateral sclerosis (ALS), progressive muscular atrophy, and traumatically damaged adult motor axons (Sumner, 1975;Ikemoto et al, 1994;Sasaki and Maruyama, 1994;Ince et al, 1995;Sunico et al, 2005).…”