Indomethacin Disrupts the Formation of β-Amyloid Plaques via an α2-Macroglobulin-Activating lrp1-Dependent Mechanism.

Pei-Pei Guan,Guo-Biao Xu,Pu Wang,Liu-Qing Yang

doi:10.3390/ijms22158185

Pei-Pei Guan, Guo-Biao Xu + Show 2 more

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https://doi.org/10.3390/ijms22158185

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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.

Highlights

Alzheimer’s disease (AD) is the most diagnosed neurodegenerative disease that is considered to increase in dementia with age [1]
Untreated mice showed no preference toward the target quadrant, indicating a severe memory impairment, whereas indomethacin-treated APP/PS1 Tg mice exhibited improved behavior compared to untreated controls (Figure 1B)
Our results reveal the mechanisms by which indomethacin decreases the production and deposition of Aβ, which results in the amelioration of cognitive decline in APP/PS1 Tg mice

Summary

Introduction

Alzheimer’s disease (AD) is the most diagnosed neurodegenerative disease that is considered to increase in dementia with age [1]. Indomethacin, naproxen, ketoprofen, ibuprofen, celecoxib and rofecoxib disrupt the aggregation of Aβ [8] Apart from their inhibitory effects on the aggregation of Aβ, NSAIDs, including indomethacin, ibuprofen, sulindac and flurbiprofen, have been reported to reduce the levels of Aβ in cultured cells [9,10,11]. Consistent with these in vitro observations, NSAIDs, including ibuprofen and nitric oxide (NO)-releasing derivatives of flurbiprofen, such as HCT1026 and NCX2216, decrease the production and deposition of Aβ in chimeric mouse/human amyloid precursor protein (Mo/HuAPP695swe) and a mutant human presenilin 1 (PS1dE9) (APP/PS1) and Tg2576 mice [12]. Other NSAIDs, including indomethacin and R-flurbiprofen, inhibit the pathology of Aβ in Tg2576 mice [13,14]

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