Deciphering the Potential Neuroprotective Effects of Luteolin against Aβ1-42-Induced Alzheimer's Disease.

Sareer Ahmad,Myeong Ok Kim,Amjad Khan,Myeung Hoon Jo,Muhammad Ikram

doi:10.3390/ijms22179583

Sareer Ahmad, Myeong Ok Kim + Show 3 more

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https://doi.org/10.3390/ijms22179583

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Abstract

The current study was undertaken to unveil the protective effects of Luteolin, a natural flavonoid, against amyloid-beta (Aβ1–42)-induced neuroinflammation, amyloidogenesis, and synaptic dysfunction in mice. For the development of an AD mouse model, amyloid-beta (Aβ1–42, 5 μL/5 min/mouse) oligomers were injected intracerebroventricularly (i.c.v.) into mice’s brain by using a stereotaxic frame. After that, the mice were treated with Luteolin for two weeks at a dose of 80 mg/kg/day. To monitor the biochemical changes, we conducted western blotting and immunofluorescence analysis. According to our findings, the infusion of amyloid-beta activated c-Jun N-terminal kinases (p-JNK), p38 mitogen-activated protein kinases, glial fibrillary acidic protein (GFAP), and ionized calcium adaptor molecule 1 (Iba-1) in the cortex and hippocampus of the experimental mice; these changes were significantly inhibited in Aβ1–42 + Luteolin-treated mice. Likewise, we also checked the expression of inflammatory markers, such as p-nuclear factor-kB p65 (p-NF-kB p65 (Ser536), tissue necrosis factor (TNF-α), and Interleukin1-β (IL-1β), in Aβ1–42-injected mice brain, which was attenuated in Aβ1–42 + Luteolin-treated mice brains. Further, we investigated the expression of pro- and anti-apoptotic cell death markers such as Bax, Bcl-2, Caspase-3, and Cox-2, which was significantly reduced in Aβ1–42 + Lut-treated mice brains compared to the brains of the Aβ-injected group. The results also indicated that with the administration of Aβ1–42, the expression levels of β-site amyloid precursor protein cleaving enzyme (BACE-1) and amyloid-beta (Aβ1–42) were significantly enhanced, while they were reduced in Aβ1–42 + Luteolin-treated mice. We also checked the expression of synaptic markers such as PSD-95 and SNAP-25, which was significantly enhanced in Aβ1–42 + Lut-treated mice. To unveil the underlying factors responsible for the protective effects of Luteolin against AD, we used a specific JNK inhibitor, which suggested that Luteolin reduced Aβ-associated neuroinflammation and neurodegeneration via inhibition of JNK. Collectively, our results indicate that Luteolin could serve as a novel therapeutic agent against AD-like pathological changes in mice.

Highlights

Alzheimer’s disease (AD) is a life-threatening disease, characterized by the loss of memory and cognitive functions [1,2]
To evaluate the effect of Luteolin against Aβ1–42-induced neuroinflammation, we analyzed the expression of p-Jun N-terminal kinase (JNK)/p-38, Glial fibrillary acid protein (GFAP), and Ionized calcium-binding adaptor molecule 1 (Iba-1) in the cortex and DG (Dentate Gyrus) region of the hippocampus of the experimental mice, as these structures play a key role in neurodegeneration [28,29]
We checked the expression of GFAP and Iba-1 in the brains of the experimental mice and found that in the brains of Aβ1–42-injected mice, the expression of these markers was significantly upregulated, while it was reduced in the brains of Aβ1–42 + Luteolintreated mice

Summary

Introduction

Alzheimer’s disease (AD) is a life-threatening disease, characterized by the loss of memory and cognitive functions [1,2]. Neuroinflammation is manifested through several events, such as activation of the innate immune system and of microglial and astrocytic cells, which induce the release of inflammatory mediators and cytokines [5,6]. The inflammatory cytokines induce mitochondrial apoptosis, manifested by the release of the cytochrome C, the suppression of the B cell lymphoma 2 (Bcl-2), the activation of caspases [9,10]. It plays a significant role in neuronal apoptosis in neurodegenerative diseases by integrating death signals through Bcl-2/Bax and coordinates caspases through the release of Cytochrome C. Bcl-2 modulates the translocation of the pro-apoptotic protein Bax from the cytosol to the mitochondrial membrane, where it enhances mitochondrial membrane permeability and releases Cyt C, which further promotes pro-caspases activation [11]

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