Christine Kivnani

 Introduction: Alzheimer’s disease (AD) is an irreversible neurodegenerative disorder. It is estimated that more than 5.4 million people in the US are affected by AD₁. With a rapid growth of an aging population, this will become an even bigger problem in society. The current standard of care is minimally effective and there is no cure for AD₃. The pathological hallmarks of AD are amyloid-beta plaques, neurofibrillary tangles, neuronal degeneration, and neuroinflammation₄. These lead to chronic activation of microglia and cause their function to shift from homeostatic surveillance, monitoring, and clearing debris to pathological₄. Aberrant microglia have an upregulation of RIPK1, which causes lysosomal inhibition and promotion of inflammation, amyloid-beta plaque accumulation, and synaptic loss₂. This study examines if RIPK1 inhibition can restore function of microglia to slow the progression of AD pathology and symptoms₂. Methods₂: Nec-1s is a highly soluble, CNS specific RIPK1 inhibitor. Either vehicle or Nec-1s was dissolved into a solution and put into the drinking water of APP/PS1 AD mice for 1 month. Thioflavin-S+ staining was used to visualize and compare the number of amyloid-beta plaques. A Morris water maze required mice to use visual cues to locate a submerged platform in a pool of water and demonstrate their spatial memory. Microglia from wildtype mice were isolated and treated with AB42 in the presence of vehicle or Nec-1s, then TNFa levels were measured to assess changes in the microglial secretion of pro-inflammatory cytokines. Results₂: Visualization of AB-plaques showed a statistically significant decrease in the number of immunoreactive AB-plaques developed in Nec-1s treated mice₁ After 4 days of repeated Morris water maze tests, Nec-1s treated APP/PS1 mice showed quicker responses and performed comparably to the wildtype mice, suggesting that there was improvement in cognition. Decreased levels of TNFa were detected from microglia that were administered AB42 and Nec-1s, suggesting a downregulation of the inflammatory response. Conclusions₂: RIPK1 inhibitors, such as Nec-1s, can restore microglia function and reduce AD pathology. Nec-1s can potentially reduce AB plaque development, improve spatial memory, and reduce neuroinflammation. This is likely not a cure, but should be researched as a potential therapy to slow progression of AD. The mice in this study were only treated with the RIPK1 inhibitor for 1 month so long-term studies and human clinical trials are necessary to assess the effectiveness of RIPK1 inhibitors as a viable treatment.

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