ALZHEIMERS RESEARCH PROJECT: Immune and inflammatory interactions in Alzheimer's disease-related dementias

National Institute On Aging

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Abstract

During FY25 we accomplished the following: 1) We repeated with female 5xFAD and control mice the experiment to check the effects of gut-initiated inflammation on brain pathology and behavior. We found that low dose dextran sodium sulfate treatment led to gene expression changes in the brain, especially in hippocampus and cortex, and less so in microglia. Thus, gut inflammation affects the brain. However, there were no statistically significant differences in behavior (open field test, home cage activity) and no differences in the extent of plaque deposition in 5xFAD brains. We followed up by testing two hypotheses suggested by these results: a) different kinds of inflammatory insults have different effects or b) the acute nature of brain pathology in the 5xFAD mice may have precluded experimental observation of an effect of gut-initiated inflammation. 2) We carried out the entire DSS experiment with male 5xFAD and control mice. Brain tissue was harvested for IHC and transcriptional assays, microglia were purified for RNA assays and hematopoietic cells were analyzed by multi-dimensional flow cytometry. Similar assays were conducted with young and old control mice to determine the extent to which DSS-induced low grade inflammation mimicked the effects of chronc age-associated inflammation. 3) We carried out kinetic studies of the effects of LPS in a microglial cell line. RNA isolated at various times after activation was used in RNA-Seq and we carried ChIP-seq with anti-RelA antibodies to query the role of NF-kB activation in these cells. A third component of the experiment, to block NF-kB activation, that had been unsuccessful last year was re-initiated by a new post-doctoral fellow. We found that inhibiting NF-kB activation using a pharmacologic inhibitor of IkB kinase induced cell death. Our preliminary interpretation is that LPS is a death-inducing stimulus for microglia from which cells are rescued by NF-kB activity. We are currently exploring mechanism of this phenomenon and extending the observations to primary cells. 4)One interpretation of the lack of a substantive effect of DSS on amyloid deposition in 5xFAD mice was that amyloid patholigy is acute in this strain, leading to the hypothesis that slowing down amyloid pathology (as it occurs during during the prodromal phase of AD) may be a more appropriate system in which to study the effects of chronic inflammation. For this we initiated a colony of 3xtransgenic mice that have a longer phase of amyloid buildup.