NEUROINFLAMMATORY MECHANISMS INVOLVED IN THE EARLY DEVELOPMENT AND PROGRESSION OF ALZHEIMER’S DISEASE

Abstract

Alzheimer disease is an example of a progressive type of neurodegenerative disease, neuroinflammation has been one of the pathogenic processes and the mechanism of transition between protective and destructive inflammation as well as the period of transition have not been fully clarified. This paper explored longitudinal evaluation of neuroinflammatory response using a 5xFAD transgenic mouse model of 2 and 18 months age by a comprehensive group of quantitative measures of the glial activity states, cytokine network activities, inflammasome activities, signaling pathway activities, synaptic integrity or blood-brain barrier functionality. Outcomes discovered a discrete transition between phases that interacted 6-9 months, was an inversion of M1:M2 microglial polarization index of 0.67 to 1.28, cross of the TNF-alpha:IL-10 ratio of 0.63 to 1.75, and a 5.9-fold increase in NLRP3 inflammasome activity. It was observed that at the critical level of approximately 180 pmol per gram of accumulation of the Amyloid- 2 in the brain, the pro-inflammatory cytokines started increasing exponentially and the anti-inflammatory mediators started decreasing exponentially. Hierarchical clustering revealed that there were three different molecular modules pro-inflammatory mediators, anti-inflammatory-synaptic integrity factors and amyloid pathology and high negative correlation between pro-inflammatory and synaptic modules. The long term consequences of NF-?-activation were found to be cellular processes leading to chronic inflammation.B and p 38 MAPK signaling and counter-intuitive AKT-mTOR pro-survival signaling inhibition. M1:M2 polarization inhibition and neutralization of NLRP3 and TNF-a therapeutic intervention of the transition window led to the expression of synaptic proteins, and cognitive performance by 64 and 71 percent, respectively, of vehicle controls. The above results characterize neuroinflammation in Alzheimer disease as a threshold-based transition between a protective and detrimental state that is elicited by amyloid-b deposition, inflammasome activation and long-term maintenance of a pro-inflammatory signal and window of transition characterizes a disease modulation therapeutic window.