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- W3188786131 abstract "Epidemiological studies have implied that the nonsteroidal anti-inflammatory drug (NSAID) indomethacin slows the development and progression of Alzheimer’s disease (AD). However, the underlying mechanisms are notably understudied. Using a chimeric mouse/human amyloid precursor protein (Mo/HuAPP695swe) and a mutant human presenilin 1 (PS1-dE9) (APP/PS1) expressing transgenic (Tg) mice and neuroblastoma (N) 2a cells as in vivo and in vitro models, we revealed the mechanisms of indomethacin in ameliorating the cognitive decline of AD. By screening AD-associated genes, we observed that a marked increase in the expression of α2-macroglobulin (A2M) was markedly induced after treatment with indomethacin. Mechanistically, upregulation of A2M was caused by the inhibition of cyclooxygenase-2 (COX-2) and lipocalin-type prostaglandin D synthase (L-PGDS), which are responsible for the synthesis of prostaglandin (PG)H2 and PGD2, respectively. The reduction in PGD2 levels induced by indomethacin alleviated the suppression of A2M expression through a PGD2 receptor 2 (CRTH2)-dependent mechanism. Highly activated A2M not only disrupted the production and aggregation of β-amyloid protein (Aβ) but also induced Aβ efflux from the brain. More interestingly, indomethacin decreased the degradation of the A2M receptor, low-density lipoprotein receptor-related protein 1 (LRP1), which facilitated the brain efflux of Aβ. Through the aforementioned mechanisms, indomethacin ameliorated cognitive decline in APP/PS1 Tg mice by decreasing Aβ production and clearing Aβ from the brains of AD mice." @default.
- W3188786131 created "2021-08-16" @default.
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- W3188786131 creator A5052747073 @default.
- W3188786131 creator A5063192101 @default.
- W3188786131 creator A5083163988 @default.
- W3188786131 date "2021-07-30" @default.
- W3188786131 modified "2023-10-17" @default.
- W3188786131 title "Indomethacin Disrupts the Formation of β-Amyloid Plaques via an α2-Macroglobulin-Activating lrp1-Dependent Mechanism" @default.
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- W3188786131 doi "https://doi.org/10.3390/ijms22158185" @default.
- W3188786131 hasPubMedCentralId "https://www.ncbi.nlm.nih.gov/pmc/articles/8348656" @default.
- W3188786131 hasPubMedId "https://pubmed.ncbi.nlm.nih.gov/34360951" @default.
- W3188786131 hasPublicationYear "2021" @default.
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