Aleksandr Pereverzev

Introduction. Alzheimer’s disease (AD) is the most common type of dementia¹ and is characterized by amyloid-β (Aβ ) plaques, tau tangles, brain atrophy, and neuroinflammation². The most accepted model of disease progression is the “amyloid-β cascade hypothesis” which identifies Aβ  deposits as the main cause of neurologic dysfunction¹. The current clinical treatments for AD are cholinesterase inhibitors and memantine, a NMDA receptor inhibitor³. The NLRP3 inflammasome has been associated with AD pathology is found in microglia and is composed of an NLRP3 protein that recruits ASC, which in turn recruits pro-caspase-1 which is cleaved to caspase-1 which in turn cleaves IL-1β into its active form^4,5. A better understanding of NLRP3, Aβ , and Tau may reveal new insight into mechanisms and therapies. Methods. Human fetal microglia were incubated with Aβ , amylin, and an amylin-receptor inhibitor⁶. Aβ  oligomers and protofibrils were incubated with mouse microglia⁷. Pre-aggregated Tau was incubated with mouse microglia, some wild-type and some with Asc deficiencies⁴. APP/PS1 mice had their brains compared to APP/PS1;ASC^-/- mice with antibody staining. Purified ASC protein was injected into one hippocampus of APP/PS1 mice, with the contralateral used as a control⁸. Tau22 were compared to Tau22 mice with an Nlrp3 or Asc knockout with ThioS and AT8 staining and Morris Water Maze (MWM) to assess spatial learning and memory⁹. Dihydromyricetin (DHM) was administed to APP/PS1 mice with tissue samples and experiments conducted at two and four weeks to evaluate microglial and NLRP3 activation, Aβ  deposits, and cognitive function¹⁰. Results. Amylin and Aβ  were both able to activate NLRP3, IL-1β, and caspase-1 production in human fetal microglia⁶. Aβ  oligomers and protofibrils increased IL-1β production which was turned of by an inflammasome inhibitor⁷. Pre-aggregated tau increased IL-1β production in mouse wild-type microglia and not in Asc-deficient microglia⁴. APP/PS1;Asc^-/- mice had fewer Aβ  deposits than APP/PS1 mice. Hippocampi injected with purified ASC had more Aβ  deposits than the contralateral hippocampus⁸. Tau22 mice with Nlrp3 or Asc deficiencies had fewer Tau deposits and higher scores on the MWM⁹. APP/PS1 mice treated with DHM had fewer activated microglia, less NLRP3 production, fewer Aβ  deposits, and fewer pro-inflammatory microglia¹⁰. Conclusion. The NLRP3 inflammasome can both be activated by Aβ and Tau presence and aggravate pathology and results support manipulation of NLRP3 as a therapeutic approach. AD etiology is still under debate¹¹, and hopefully more research into the NLRP3 inflammasome can lead to a better understanding of AD and development of treatments.

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