Abstract:Cellular processing of the amyloid precursor protein (APP) has been extensively studied, but its precise function remains elusive. The intracellular domain of APP has been proposed to regulate expression of several genes by mechanisms that are largely unknown. We report that APP regulates expression of the aquaporin 1 (AQP1) gene in mouse embryonic fibroblasts and in transgenic mice. AQP1 mRNA and protein were down-regulated in fibroblasts lacking APP or presenilin 2 in which AQP1 expression was restored by st… Show more
“…Overexpression of AQP1 has been evidenced in autoimmune and alcoholic pancreatitis (42), in Alzheimer disease (43), as well as in rheumatoid and psoriatic arthritis cases (44). AQP4 expression is enhanced in the brain of Alzheimer disease patients and cerebral amyloid angiopathy patients (43,45).…”
Section: Discussionmentioning
confidence: 99%
“…Overexpression of AQP1 has been evidenced in autoimmune and alcoholic pancreatitis (42), in Alzheimer disease (43), as well as in rheumatoid and psoriatic arthritis cases (44). AQP4 expression is enhanced in the brain of Alzheimer disease patients and cerebral amyloid angiopathy patients (43,45). AQP5 polymorphisms have been associated with chronic obstructive pulmonary disease and chronic inflammation in smoking patients and survival rate in severe sepsis (46,47).…”
Background: Aquaporins are channels permeable to water, and they are essential for immune cell migration. Results: We demonstrate that aquaporin-mediated water fluxes are necessary for the NLRP3 inflammasome-dependent release of mature IL-1 in vitro and in vivo. Conclusion: Aquaporins are implicated in the mechanisms of proinflammatory cytokine secretion during inflammation. Significance: The discovery of a new function for AQPs opens new diagnostic and therapeutic opportunities in inflammatory disorders.
“…Overexpression of AQP1 has been evidenced in autoimmune and alcoholic pancreatitis (42), in Alzheimer disease (43), as well as in rheumatoid and psoriatic arthritis cases (44). AQP4 expression is enhanced in the brain of Alzheimer disease patients and cerebral amyloid angiopathy patients (43,45).…”
Section: Discussionmentioning
confidence: 99%
“…Overexpression of AQP1 has been evidenced in autoimmune and alcoholic pancreatitis (42), in Alzheimer disease (43), as well as in rheumatoid and psoriatic arthritis cases (44). AQP4 expression is enhanced in the brain of Alzheimer disease patients and cerebral amyloid angiopathy patients (43,45). AQP5 polymorphisms have been associated with chronic obstructive pulmonary disease and chronic inflammation in smoking patients and survival rate in severe sepsis (46,47).…”
Background: Aquaporins are channels permeable to water, and they are essential for immune cell migration. Results: We demonstrate that aquaporin-mediated water fluxes are necessary for the NLRP3 inflammasome-dependent release of mature IL-1 in vitro and in vivo. Conclusion: Aquaporins are implicated in the mechanisms of proinflammatory cytokine secretion during inflammation. Significance: The discovery of a new function for AQPs opens new diagnostic and therapeutic opportunities in inflammatory disorders.
“…While, these studies are in direct contrast to our observation of hyperacetylation and downregulation of Bdnf expression, it is by no means a novel phenomenon. Huysseune et al (2009) recently showed that hyperacetylation induced by TSA treatment in mouse fibroblasts that express APP actually decreases the mRNA levels of aquaporin 1 and this downregulation is dependent on de novo protein synthesis, suggesting that a repressive element is upregulated after TSA treatment. Therefore, it is reasonable to deduce that the increased hyperacetylation we observe in cultured neurons in this study is either not substantially contributing to Bdnf promoter regulation or that some other repressive protein(s) upregulated by increased histone acetylation may be acting to diminish Bdnf mRNA levels.…”
With aging and Alzheimer's disease (AD), there is an increased sensitivity to stress along with declines in the memory-associated neurotrophin brainderived neurotrophic factor in AD. We have replicated this aging phenotype in cultured neurons from aged mice despite being grown in the same environmental conditions as young neurons. This led us to hypothesize that age-related differences in epigenetic acetylation and methylation of histones are associated with age-related gene regulation. We cultured hippocampal/ cortical neurons from the 3xTg-AD mouse model and from non-transgenic mice to quantify single cell acetylation and methylation levels across the life span. In non-transgenic neurons, H3 acetylation was unchanged with age, while H4 acetylation decreased with age of the donor. Compared to nontransgenic neurons, 3xTg-AD neurons had higher levels of H3 and H4 acetylation beginning at 4 months of age. In contrast to non-transgenic neurons, 3xTg-AD neurons increased acetylation with age; 3xTg-AD neurons also responded differently to inhibition of histone deacetylases at an early age. Importantly, treatment of non-transgenic neurons with the AD peptide Aβ also elevated levels of acetylation. We also examined the repressive function of histone H3 lysine 9 (H3K9) methylation. H3K9 methylation increased with age in non-transgenic neurons, which was amplified further in 3xTg-AD neurons. The dominant effect of higher H3K9 methylation was supported by lower Bdnf gene expression in non-transgenic and 3xTg-AD mice. These data show that the epigenetic states of non-transgenic and 3xTg-AD brain neurons are profoundly different and reversible, beginning at 4 months of age when the first memory deficits are reported.
“…This suggestion gave rise to conflicting results and interpretations, 9,10 but very recent work unraveled new genes regulated by AICD and showed that their regulation relies on an epigenetic mechanism. 30,31 Although this mechanism awaits further characterization, cleavage at ε site and AICD could play an essential role in APP function or during AD, independently of Aβ, by controlling gene expression. It is therefore of prime interest to understand if dimerization has similar regulatory roles in Aβ and AICD production.…”
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