Neuroprotective Effect of Fisetin Against Amyloid-Beta-Induced Cognitive/Synaptic Dysfunction, Neuroinflammation, and Neurodegeneration in Adult Mice

Abstract

Alzheimer's disease (AD) is a devastating and progressive neurodegenerative disease and is characterized pathologically by the accumulation of amyloid beta (Aβ) and the hyperphosphorylation of tau proteins in the brain. The deposition of Aβ aggregates triggers synaptic dysfunction, hyperphosphorylation of tau, and neurodegeneration, which lead to cognitive disorders. Here, we investigated the neuroprotective effect of fisetin in the Aβ mouse model of AD. Single intracerebroventricular injections of Aβ (3 μl/5 min/mouse) markedly induced memory/synaptic deficits, neuroinflammation, and neurodegeneration. Intraperitoneal injections of fisetin at a dose of 20 mg/kg/day for 2 weeks starting 24 h after Aβ injection significantly decreased the Aβ-induced accumulation of Aβ, BACE-1 expression, and hyperphosphorylation of tau protein at serine 413. Fisetin treatment also markedly reversed Aβ-induced synaptic dysfunction by increasing the levels of both presynaptic (SYN and SNAP-25) and postsynaptic proteins (PSD-95, SNAP-23, p-GluR1 (Ser 845), p-CREB (Ser 133) and p-CAMKII (Thr 286) and ultimately improved mouse memory, as observed in the Morris water maze test. Fisetin significantly activated p-PI3K, p-Akt (Ser 473), and p-GSK3β (Ser 9) expression in Aβ-treated mice. Moreover, fisetin prevented neuroinflammation by suppressing various activated neuroinflammatory mediators and gliosis; it also suppressed the apoptotic neurodegeneration triggered by Aβ injections in the mouse hippocampus. Fluorojade-B and immunohistochemical staining for caspase-3 revealed that fisetin prevented neurodegeneration in Aβ-treated mice. Our results suggest that fisetin has a potent neuroprotective effect against Aβ-induced neurotoxicity. These results demonstrate that polyphenolic flavonoids such as fisetin could be a beneficial, effective and safe neuroprotective agent for preventing neurological disorders such as AD.

FGF21 Attenuates High-Fat Diet-Induced Cognitive Impairment via Metabolic Regulation and Anti-inflammation of Obese Mice

“…It has been reported that the Akt/GSK-3β pathway plays a vital role in mediating neuroinflammation in the hippocampus, which likely contributes to obesity and diabetes in aging mice [51, 52]. We thus measured activation of Akt/GSK-3β signaling in the hippocampus by western blot analysis.…”

Metabolic Stress Alters Antioxidant Systems, Suppresses the Adiponectin Receptor 1 and Induces Alzheimer’s Like Pathology in Mice Brain

“…As depicted in Figure 6a, the expression level of PSD-95 was significantly decreased in both the cortex and hippocampus of the HFD-fed group in comparison with the control group. A presynaptic protein marker (synaptosomal-associated protein 23 (SNAP-23) that plays a vital role in synaptic plasticity [59] was also analyzed through Western blot analysis. Consistent with the previous findings, the expression of (SNAP-23) in both the cortex and hippocampus was decreased in the HFD-fed group in comparison with the control group (Figure 6a).…”

Neurotoxic Agent-Induced Injury in Neurodegenerative Disease Model: Focus on Involvement of Glutamate Receptors

“…Recently, many neurotoxic agents have been employed in experiments in order to explore cellular functions and dysfunctions (Kumar and Kumar, 2010; van der Star et al, 2012; Abbasi et al, 2013; Jiang et al, 2015; Parekh, 2015; Ahmad et al, 2017; Kim et al, 2017). Their correlation with pathological characteristics of diseases via the utilization of neurotoxic agent-induced models is a helpful way to screen and discover potential therapeutic drugs for NDDs.…”