PROJECT SUMMARY/ABSTRACT Alzheimer?s disease (AD) is a neurodegenerative disease that results in amyloid ? plaque deposition, neurofibrillary tangle (NFT) formation and life-altering cognitive defects. Many human genetic AD risk factors, including APOE and TREM2, modulate neuroinflammation and/or the function of microglia, the central nervous system (CNS) resident innate immune cell. This suggests that microglia and inflammation are key players in shaping AD. Our recent transcriptomic work has revealed that Spp1, which encodes the protein osteopontin (OPN), is upregulated in microglia during aging, amyloidosis and tauopathy, with further increases in aged females over aged males. All of these contexts represent AD risk factors or AD associated pathologies, suggesting that Spp1 may play a significant role in disease. To date little is known regarding how OPN functions in microglia and AD pathology. Using primary microglial cultures, we have demonstrated that OPN plays a pro-inflammatory role following stimulation with inflammatory mediators such as lipopolysaccharide (LPS) or aggregated tau. Additionally, Spp1-/- mice (which do not express Spp1 and therefore lack OPN) have reduced neuroinflammation following a systemic inflammatory challenge with LPS, again indicating a pro- inflammatory role for this protein. We hypothesize that Spp1 expression during amyloidosis and tauopathy significantly alters cognition, neuroinflammation, gliosis and other CNS sequelae observed in these settings. To address this hypothesis, we will assess mice in the context of amyloidosis using wild type (WT) control mice, APP/PS1 mice (which develop amyloidosis) that either have normal expression of Spp1 or that lack Spp1 expression (Spp1-/-), and therefore do not express OPN, or in a tauopathy model again in the presence or absence of Spp1 expression. We will assess multiple parameters including behavioral/ cognitive performance (using open field assay, elevated plus maze, contextual fear conditioning and Morris water maze), immunofluorescence/ immunohistology examining plaque deposition and gliosis, tau phosphorylation, western blot analysis for total and phosphorylated tau and RT-qPCR to examine cortical and hippocampal gene expression of proinflammatory and anti-inflammatory factors. Furthermore, we will be using single cell transcriptomics to examine the entire RNA transcriptome on a per cell basis to assess the impact of Spp1 expression on microglial transcriptomes during amyloidosis or tauopathy. Our proposed work will be the first to define the role of Spp1 in behavior/cognition, neuroinflammation and gliosis during amyloidosis or tauopathy and will also determine how it shapes microglial transcriptomes within these contexts. This work will provide highly novel insights a potentially important molecular modulator of disease, and could provide the impetus to examine new therapeutic measures for management/alleviation of AD associated CNS sequelae.
- National Institute on Aging: $430,375.00
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