<p class="first" id="d8795889e142">Pathologic inflammation in response to injury,
infection, or oxidative stress is a
proposed mechanism relating cognitive decline to dementia. The kynurenine pathway
and thioredoxin-interacting protein (TXNIP) activity regulate inflammation and neurotoxicity
in Alzheimer disease (AD). We examined cognitive deficits, kynurenine pathway mediators,
TXNIP, and oxidative damage in the cerebrum and spleen, including inflammatory cytokine
production by stimulated splenocytes, from female triple transgenic (3xTg-AD) mice
in early and late stages of disease progression, and characterized tissue-specific
epigenetic regulation of Txnip gene expression. We show that cognitive deficits in
7-month-old 3xTg-AD mice are associated with a stable increase in cerebrum and spleen
tryptophan metabolites, with a concomitant increase in amyloid β 40 (Aβ40)/Aβ42 and
tau/hyperphosphorylated tau pathologies and a coordinated reduction in spleen proinflammatory
cytokine production in 17-month-old mice. The enhanced cerebrum TXNIP expression is
associated with increased histone acetylation, transcription factor [Aβ42 or CCCTC-binding
factor (CTCF)] binding, and Txnip promoter hypomethylation, whereas the attenuated
spleen TXNIP expression is associated with increased histone methylation, reduced
CTCF binding, and Txnip promoter hypermethylation. These results suggest a causal
relationship among epigenomic state, TXNIP expression, cerebral-spleen tryptophan
metabolism, inflammatory cytokine production, and cognitive decline; and they provide
a potential mechanism for Txnip gene regulation in normal and pathologic conditions,
suggesting TXNIP levels may be a useful predictive or diagnostic biomarker for Aβ40/Aβ42
targeted AD therapies.
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