Karthik Mouli

Introduction: Alzheimer’s Disease is a neurodegenerative disease that is the leading cause of dementia in the United States¹. Alzheimer’s Disease is classically associated with the extracellular accumulation of amyloid-β plaques and hyperphosphorylated tau neurofibrillary tangles, yet a growing body of evidence points toward neuroinflammation – specifically chronic microgliosis and microglial-mediated neuritis –  as a core feature of Alzheimer’s Disease pathophysiology as well^1,3,5.  While microglia are essential for maintaining neuron-environment homeostasis , the extracellular accumulation of amyloid-β results in their pro-inflammatory activation^3,6,7.  Recent studies have shown that extracellular amyloid-βactivates microglia via an NLRP3 inflammasome-dependent mechanism, leading to microglial pyroptosis and the release of the pro-inflammatory cytokines IL-1β and IL-18.  Via this mechanism, it was hypothesized that the NLRP3 inflammasome mediates Alzheimer’s – associated neuroinflammation and demyelination, leading to cognitive decline.  Methods: A mouse model containing human transgenic APP and PS1 (APP/PS1) was used to replicate Alzheimer’s Disease pathophysiology and was fed an orally-active NLRP3 inhibitor (OLT1177)⁸. Post-mortem cortical slices were obtained and immunohistochemically stained to analyze microglial, oligodendrocytic and amyloid plaque localization, as well as ELISA analysis of cytokine release  to determine microglial activation phenotype⁸. APP/PS1 and WT mice were assessed for visuospatial memory function using the Morris Water Maze (MWM) test^8,9.  In separate experiments to identify priming factors for the NLRP3 inflammasome, ex vivo microglia from APP/PS1 mice were treated with zinc chelators and analyzed via Western Blot for inflammasome activation products, and APP/PS1 mice fed zinc-deficient diets were assessed on the Y-maze visuospatial task¹⁰.  Results:  OLT1177 inhibition of NLRP3 inflammasome activity reduces microglial activation and the number of cortical amyloid- β plaques in APP/PS1 mice, as well as improving MWM test scores⁸. Colocalization of IL- 1β, Gasdermin D and other markers of NLRP3 inflammasome activation were most notable in brain tissue regions where oligodendrocyte markers were absent, suggesting an association between NLRP3 activation and oligodendrocyte pyroptosis⁹. Oligodendrocyte NLRP3 activation occurs via Drp1-mediated inhibition of glycolytic pathways⁹ and dietary zinc deficiency is sufficient to prime microglial NLRP3 activation and significantly decrease Y-maze performance¹⁰.  Significance: These findings suggest that the NLRP3 inflammasome has an integral role in mediating the progression and severity of Alzheimer’s Disease through demyelination and neuroinflammation, and its activity is potentiated in the context of metabolic dysregulation and nutritional deficiency. These studies support direct NLRP3 inhibition and dietary zinc supplementation as promising new avenues to treat Alzheimer’s-associated cognitive decline by addressing its molecular roots.

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