MAR 11, 2020 10:30 AM PDT

Innate immunity in chronic neurodegeneration

Sponsored by: NanoString Technologies


The accumulation of neurotoxic amyloid beta peptides and/or neurofibrillary tangle formation are key pathological hallmarks of neurodegenerative diseases including but not limited to Alzheimer’s disease, frontotemporal dementia and multi-system atrophy. The brain has been considered as an immune-privileged organ, however, increasing evidence from translational, genetic, and pathological studies suggests that activation of distinct innate immune pathways are a third important disease hallmark which, once initiated, actively contributes to progression and chronicity of neurodegenerative disease.

Microglia play a pivotal role in this immune response and are activated by binding of aggregated proteins or aberrant nucleic acids to pattern recognition receptors. This immune activation leads to the release of inflammatory mediators, but also distracts microglia cells from their physiological functions and tasks, including debris clearance and trophic factor support. NLRP3 inflammasome activation and release of ASC specks contribute to spreading of pathology and impair microglia clearance mechanisms, and together contribute to neuronal spine loss, neuronal degeneration, and ultimately to spatial memory deficits. In keeping with this immune hypothesis of neurodegeneration, inhibition of this and other immune pathways protect from neurodegeneration in cellular and murine models of neurodegenerative disease. Modulation of the microglia driven innate immune response at key signaling steps might therefore be protective and alter disease progression. However, the microglia are not a stable population, but have continuous turn over, most likely resulting in more than one generation of microglia being involved in disease progression.  Moreover their turnover is increased in response to neurodegeneration. Along with the regional diversity of microglia, these phenomena need to be understood in more detail prior to targeting innate immune mechanisms for therapeutic purposes.

You May Also Like
Loading Comments...