Microglia centered pathogenesis in ALS: insights in cell interconnectivity

Abstract

Amyotrophic lateral sclerosis (ALS) is the most common and most aggressive form of adult motor neuron (MN) degeneration. The cause of the disease is still unknown, but some protein mutations have been linked to the pathological process. Loss of upper and lower MNs results in progressive muscle paralysis and ultimately death due to respiratory failure. Although initially thought to derive from the selective loss of MNs, the pathogenic concept of non-cell-autonomous disease has come to the forefront for the contribution of glial cells in ALS, in particular microglia. Recent studies suggest that microglia may have a protective effect on MN in an early stage. Conversely, activated microglia contribute and enhance MN death by secreting neurotoxic factors, and impaired microglial function at the end-stage may instead accelerate disease progression. However, the nature of microglial–neuronal interactions that lead to MN degeneration remains elusive. We review the contribution of the neurodegenerative network in ALS pathology, with a special focus on each glial cell type from data obtained in the transgenic SOD1G93A rodents, the most widely used model. We further discuss the diverse roles of neuroinflammation and microglia phenotypes in the modulation of ALS pathology. We provide information on the processes associated with dysfunctional cell–cell communication and summarize findings on pathological cross-talk between neurons and astroglia, and neurons and microglia, as well as on the spread of pathogenic factors. We also highlight the relevance of neurovascular disruption and exosome trafficking to ALS pathology. The harmful and beneficial influences of NG2 cells, oligodendrocytes and Schwann cells will be discussed as well. Insights into the complex intercellular perturbations underlying ALS, including target identification, will enhance our efforts to develop effective therapeutic approaches for preventing or reversing symptomatic progression of this devastating disease.

Effect and Disease Indicative Role of Inflammation in Neurodegenerative Pathology: A Mechanistic Crosstalk of Promise and Dilemma

“…PET imaging study also established the similar result of microglia activation [79]. In vivo studies found microgliosis in different motor regions of the brain and dorsolateral perfrontal cortex and thalamus [80]. Recent finding in transgenic mice model showed aggregation and mislocalisation of toxic protein aggregates in motor neurons, which triggers microglia and astrocytes mediated inflammatory processes [76].…”

Neuroimmune and Inflammatory Signals in Complex Disorders of the Central Nervous System

“…During the symptomatic phase of ALS, microglia are characterized by proliferation and transformation into phagocytic cells, displaying a morphology similar to that of macrophages in the periphery [118, 119]. They can form clusters of proliferating microglia adjacent to the damaged motor neurons [120, 121], thus playing a preponderant pathogenic role during the progression of ALS [122, 123]. In a mouse model of ALS expressing mutant SOD1, genetic excision of the mutated protein only in myeloid cells and microglia results in a slower paralysis progression as compared with mice expressing the mutant protein in microglia [124].…”

Exosomes: potential model for complement-stealth delivery systems

“…Exosomal communication between microglia and neurons of the brain is a way for the central nervous system to modulate the pathology of amyotrophic lateral sclerosis, which is the most common and most aggressive form of adult motor neuron degeneration (33). Exosomes can be a reason behind drug resistance in neurological diseases and cancer, an example of this can be found in the treatment of multiple myeloma (34).…”