Parkinson's disease: Microglial/macrophage-induced immunoexcitotoxicity as a central mechanism of neurodegeneration

Abstract

Parkinson's disease is one of the several neurodegenerative disorders that affects aging individuals, with approximately 1% of those over the age of 60 years developing the disorder in their lifetime. The disease has the characteristics of a progressive disorder in most people, with a common pattern of pathological change occurring in the nervous system that extends beyond the classical striatal degeneration of dopaminergic neurons. Earlier studies concluded that the disease was a disorder of alpha-synuclein, with the formation of aggregates of abnormal alpha-synuclein being characteristic. More recent studies have concluded that inflammation plays a central role in the disorder and that the characteristic findings can be accounted for by either mutation or oxidative damage to alpha-synuclein, with resulting immune reactions from surrounding microglia, astrocytes, and macrophages. What has been all but ignored in most of these studies is the role played by excitotoxicity and that the two processes are intimately linked, with inflammation triggered cell signaling enhancing the excitotoxic cascade. Further, there is growing evidence that it is the excitotoxic reactions that actually cause the neurodegeneration. I have coined the name immunoexcitotoxicity to describe this link between inflammation and excitotoxicity. It appears that the two processes are rarely, if ever, separated in neurodegenerative diseases.

Updates on immunity and inflammation in Parkinson disease pathology

“…Occurrence of pathological event may cause the activation of microglia along with initiation of various mechanisms which contribute in continuous scanning of brain parenchyma as well as cross talk with neurons. Recently, microglia‐induced immunoexcitotoxicity has been suggested as a central mechanism of neurodegeneration in PD pathology (Blaylock, ). Neuron and microglia interaction is dual, and healthy neurons support the microglia to remain in the quiescent state, through membrane‐bound signals like CD200 and CX3CL1 and through secretion of neurotransmitters and neurotrophins (Hanisch & Kettenmann, ; Raivich ).…”

“…Recently, microglia-induced immunoexcitotoxicity has been suggested as a central mechanism of neurodegeneration in PD pathology (Blaylock, 2017). Neuron and microglia interaction is dual, and healthy neurons support the microglia to remain in the quiescent state, through membrane-bound signals like CD200 and CX3CL1 and through secretion of neurotransmitters and neurotrophins (Hanisch & Kettenmann, 2007;Raivich 2005).…”

Differential transcriptional profiles identify microglial- and macrophage-specific gene markers expressed during virus-induced neuroinflammation

“…As components of the innate immune response, microglia and macrophages are frequently associated with CNS pathologies such as neuroinflammation. The presence of reactive microglia and infiltration of macrophages into the CNS are often observed during brain inflammation (encephalitis), Parkinson's disease, multiple sclerosis, traumatic brain injury, and brain tumorigenesis, among others [15,[20][21][22][23][24][25]. Upon activation, macrophages can acquire distinct phenotypes such as the classically defined M1, or proinflammatory, and M2, or anti-inflammatory, polarization states.…”

SIRPα deficiency accelerates the pathologic process in models of Parkinson disease

“…Aging is a well-known risk factor for the development and progression of PD (Blaylock, 2017;Labzin, Heneka, & Latz, 2017;Matt, Lawson, & Johnson, 2016). In aged brain, microglia show altered inflammatory profiles with increased level of pro-inflammatory cytokines (Walker, Tang, & Lue, 2017).…”