Comparative Pathology of Neurodegeneration: Linking Microglial Senescence to Protein Aggregation

Abstract

The Alzheimer disease, Parkinson disease, and amyotrophic lateral sclerosis are neurodegenerative disorders that have two pathological characteristics in common: the piling up of misfolded proteins and chronic neuroinflammation. Rising evidence supports the idea that microglia, the central nervous system resident immune cells, have long been known as reactive responders but also must be regarded as active drivers of disease pathology. The following paper examines the comparative pathology of neurodegeneration among discrete disorders with an emphasis on how microglial senescence can be viewed as a unifying process coupling protein aggregation with neurodegeneration. I use analysis of post-mortem human brain tissue and pertinent animal models to determine convergent changes in microglial morphology, gene expression and secretory signature during senescence. These characteristics are dystrophic branching, defective phagocytosis ability, and pro-inflammatory cytokine up-regulation. Notably, senescence of microglia in turn also decreases the clearance of pathological aggregates like amyloid-B, a-synuclein, and TDP-43 and constitutes a feed-forward loop as the accumulation of protein deposits continues to worsen inflammatory signaling and oxidative stresses, which are further disabling microglia. Both common and disease-specific interaction between microglial senescence and aggregateprone proteins is identified by comparative evaluation. In AAD, dystrophic microglia tends to aggregate in proximity to amyloid plaques, when compared to AAD, in Parkinson, the senescence signatures are more linked to nigrostriatal Lewy bodies. Microglial senescence in ALS associates with the broad-based pathology and loss of cortical-spinal tract with TDP-43. This paper combines neuropathological data with molecular and experimental findings to propose a model framework: Microglial senescence may therefore represent an essential pivot point between protein aggregate formation and the neurodegeneration. Intervention in senescence-related pathways, in order to rejuvenate microglial function or up-regulate aggregate clearance, may be a widely applicable therapeutic approach. Together, these results emphasize the potential of the cross-disease comparative method in terms of elucidating the complicated interactions between innate immune age-related changes and proteostatic breakdown in the brain.