Abstract
Alzheimer’s disease (AD) is pathologically characterized by an excessive accumulation of amyloid-beta (Aβ) fibrils within the brain. We tested the anti-inflammatory and anti-amyloidogenic effects of (E)-2-methoxy-4-(3-(4-methoxyphenyl) prop-1-en-1-yl) phenol (MMPP), a selective signal transducer and activator of transcription 3 (STAT3) inhibitor. We examined whether MMPP (5 mg/kg in drinking water for 1 month) prevents amyloidogenesis and cognitive impairment on AD model mice induced by intraperitoneal LPS (250 μg/kg daily 7 times) injections. Additionally, we investigated the anti-neuroinflammatory and anti-amyloidogenic effect of MMPP (1, 5, and 10 μg/mL) in LPS (1 μg/mL)-treated cultured astrocytes and microglial BV-2 cells. MMPP treatment reduced LPS-induced memory loss. This memory recovery effect was associated with the reduction of LPS-induced inflammatory proteins; cyclooxygenase-2 (COX-2) and inducible nitric oxide synthase (iNOS) as well as activation of microglial cells and astrocytes in the brain. Furthermore, MMPP reduced LPS-induced β-secretase and Aβ generation. In in vitro study, LPS-induced expression of inflammatory proteins and amyloidogenic proteins was decreased in microglial BV-2 cells and cultured astrocytes by MMPP treatment. Moreover, MMPP treatment suppressed DNA binding activities of the activation of STAT3 in in vivo and in vitro. These results indicated that MMPP inhibits LPS-induced amyloidogenesis and neuroinflammation via inhibition of STAT3.
Highlights
Alzheimer’s disease (AD) is a chronic neurodegenerative disease in people over 65 years old
We discovered that methoxy-4-(3-(4-methoxyphenyl) prop-1-en-1-yl) phenol (MMPP) inhibited LPS-induced signal transducer and activator of transcription 3 (STAT3) activity and the translocation of STAT3 protein to the nucleus in both astrocytes (Fig. 5i, k) and microglial BV-2 cells (Fig. 5j, l) through Western blot and EMSA
The pathological hallmarks of neuroinflammation including marked astrogliosis, elevated release of proinflammatory mediators and cytokines appear in AD patients (Lee et al 2012a)
Summary
Alzheimer’s disease (AD) is a chronic neurodegenerative disease in people over 65 years old. There are many causes for AD, the main cause is the accumulation of betaamyloid (Aβ) which is the most toxic to brain cells. Aβ peptides are generated from amyloid precursor protein (APP) by β-site APP-cleaving enzyme 1 (BACE1) and γ-secretase. BACE1 cleaves the APP, producing a soluble APP fragment (sAPPβ) and a carboxy-terminal 99 amino acid (C99) protein. C99 is cleaved within the membrane by γ-secretase and generates Aβ and APP intracellular domain (AICD) (Gu et al 2015; Holsinger et al 2002). Aβ molecules can form flexible soluble oligomers which may exist in several forms (Schnabel 2010). Misfolded oligomers cause cell death of brain (Pulawski et al 2012)
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