Investigating neuroinflammatory markers in neurodegenerative diseases

Abstract

Neurodegenerative diseases, particularly Alzheimer's disease (AD), are the leading cause of disability and death for the aging population. The mechanisms of neurodegeneration are not fully understood although one process strongly implicated in neurodegenerative diseases is inflammation. The neuroinflammatory response is mediated by activation of glial cells, within which an activation of the NLRP3 inflammasome is considered an essential component. This process results in an increase in the proinflammatory cytokines IL-1b and IL-18 via caspase-1 activation. Potassium channels Kv3.4 and THIK-1 provide an upstream regulation of this neuroinflammatory response. While in vitro and in vivo model systems provide strong support for these mechanisms in several neurodegenerative disorders, unequivocal evidence from human disease has been lacking. This research project used post-mortem brain tissue to investigate gene expression of NLRP3 inflammasome components and related factors associated with neuroinflammation in three neurodegenerative disorders: AD, Parkinson's disease (PD) and amyotrophic lateral sclerosis (ALS). Results found no evidence for NLRP3 inflammasome activation in the three diseases, but strong evidence for glial, particularly astrocyte, activation in AD. Changes in cortical gene expression for THIK-1 and Kv3.4 also support an inflammatory glial cell activation in both advanced AD and PD with dementia, not observed in the substantia nigra of the latter group. The increase in THIK-1 expression was also supported by down-regulation in DNA methylation of its corresponding gene in AD. ALS showed no significant changes in any of the molecular markers studied. A rat model of AD pathogenesis by intrahippocampal Ab oligomer injection showed substantial up-regulation of glial activation markers, NLRP3 inflammasome components, IL-1b, and THIK-1 and Kv3.4. These findings indicate a discrepancy between human post-mortem and model systems in the evidence for neuroinflammation in neurodegenerative disease. This may reflect some of the limitations of the former approach, although animal and cellular studies cannot replicate many aspects of human disease. Future studies need to elucidate the reasons behind these inconsistencies and more fully investigate the relationship of protein function in this pathway in human cohorts with clinical findings.

Date of Award	1 Aug 2022
Original language	English
Awarding Institution	The University of Manchester
Supervisor	Catherine Lawrence (Supervisor), David Brough (Supervisor) & Michael Harte (Supervisor)