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

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 Aβ1–42 mouse model of AD. Single intracerebroventricular injections of Aβ1–42 (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 Aβ1–42 injection significantly decreased the Aβ1–42-induced accumulation of Aβ, BACE-1 expression, and hyperphosphorylation of tau protein at serine 413. Fisetin treatment also markedly reversed Aβ1–42-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 Aβ1–42-treated mice. Moreover, fisetin prevented neuroinflammation by suppressing various activated neuroinflammatory mediators and gliosis; it also suppressed the apoptotic neurodegeneration triggered by Aβ1–42 injections in the mouse hippocampus. Fluorojade-B and immunohistochemical staining for caspase-3 revealed that fisetin prevented neurodegeneration in Aβ1–42-treated mice. Our results suggest that fisetin has a potent neuroprotective effect against Aβ1–42-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.

[1]  J. Spencer.  Flavonoids and brain health: multiple effects underpinned by common mechanisms , 2009, Genes & Nutrition.

[2]  Sagar H. Barage,et al.  Amyloid cascade hypothesis: Pathogenesis and therapeutic strategies in Alzheimer's disease , 2015, Neuropeptides.

[3]  M. Kim,et al.  Melatonin attenuates D‐galactose‐induced memory impairment, neuroinflammation and neurodegeneration via RAGE/NF‐KB/JNK signaling pathway in aging mouse model , 2015, Journal of pineal research.

[4]  B. Burgering,et al.  Essential Role for Protein Kinase B (PKB) in Insulin-induced Glycogen Synthase Kinase 3 Inactivation , 1998, The Journal of Biological Chemistry.

[5]  Joanna B. Strosznajder,et al.  Poly(ADP-ribose) Polymerase-1 in Amyloid Beta Toxicity and Alzheimer's Disease , 2012, Molecular Neurobiology.

[6]  D. Selkoe,et al.  Soluble protein oligomers in neurodegeneration: lessons from the Alzheimer's amyloid β-peptide , 2007, Nature Reviews Molecular Cell Biology.

[7]  Scott R. Barnum,et al.  INFLAMMATION AND ALZHEIMERS DISEASE , 2000 .

[8]  S. Koh,et al.  Amyloid-beta-induced neurotoxicity is reduced by inhibition of glycogen synthase kinase-3 , 2008, Brain Research.

[9]  J. Bureš,et al.  β-Amyloid infusion results in delayed and age-dependent learning deficits without role of inflammation or β-amyloid deposits , 2006 .

[10]  M. Kim,et al.  Protection of the Developing Brain with Anthocyanins Against Ethanol-Induced Oxidative Stress and Neurodegeneration , 2014, Molecular Neurobiology.

[11]  Yu-ping Peng,et al.  Protection of TGF-β1 against Neuroinflammation and Neurodegeneration in Aβ1–42-Induced Alzheimer’s Disease Model Rats , 2015, PloS one.

[12]  P. Maher,et al.  Fisetin Lowers Methylglyoxal Dependent Protein Glycation and Limits the Complications of Diabetes , 2011, PloS one.

[13]  M. Kim,et al.  Osmotin attenuates amyloid beta-induced memory impairment, tau phosphorylation and neurodegeneration in the mouse hippocampus , 2015, Scientific Reports.

[14]  Ki Yong Lee,et al.  Cognitive-enhancing effects of Rhus verniciflua bark extract and its active flavonoids with neuroprotective and anti-inflammatory activities. , 2013, Food and chemical toxicology : an international journal published for the British Industrial Biological Research Association.

[15]  Protective Effect of Lupeol Against Lipopolysaccharide-Induced Neuroinflammation via the p38/c-Jun N-Terminal Kinase Pathway in the Adult Mouse Brain , 2016, Journal of Neuroimmune Pharmacology.

[16]  J. Lucas,et al.  Chronic lithium administration to FTDP‐17 tau and GSK‐3β overexpressing mice prevents tau hyperphosphorylation and neurofibrillary tangle formation, but pre‐formed neurofibrillary tangles do not revert , 2006, Journal of neurochemistry.

[17]  T. Nabeshima,et al.  CREB phosphorylation as a molecular marker of memory processing in the hippocampus for spatial learning , 2002, Behavioural Brain Research.

[18]  L. Mucke,et al.  Alzheimer Mechanisms and Therapeutic Strategies , 2012, Cell.

[19]  M. D’Amelio,et al.  CREB is necessary for synaptic maintenance and learning‐induced changes of the ampa receptor GluA1 subunit , 2013, Hippocampus.

[20]  Kaishun Bi,et al.  Schisantherin A recovers Aβ-induced neurodegeneration with cognitive decline in mice , 2014, Physiology & Behavior.

[21]  T. Wyss-Coray,et al.  Inflammation in Alzheimer disease-a brief review of the basic science and clinical literature. , 2012, Cold Spring Harbor perspectives in medicine.

[22]  M. Nishizawa,et al.  Hyperphosphorylation of Tau Induced by Naturally Secreted Amyloid-β at Nanomolar Concentrations Is Modulated by Insulin-dependent Akt-GSK3β Signaling Pathway* , 2012, The Journal of Biological Chemistry.

[23]  Y. Li,et al.  Neuroglobin Attenuates Beta Amyloid-Induced Apoptosis Through Inhibiting Caspases Activity by Activating PI3K/Akt Signaling Pathway , 2015, Journal of Molecular Neuroscience.

[24]  M. Kim,et al.  Protective effects of Anthocyanins against Amyloid beta-induced neurotoxicity in vivo and in vitro , 2015, Neurochemistry International.

[25]  M. Kim,et al.  Anthocyanins Reversed D-Galactose-Induced Oxidative Stress and Neuroinflammation Mediated Cognitive Impairment in Adult Rats , 2015, Molecular Neurobiology.

[26]  P. Maher.  How fisetin reduces the impact of age and disease on CNS function. , 2015, Frontiers in bioscience.

[27]  B. Culver,et al.  Suppression of nuclear factor kappa B ameliorates astrogliosis but not amyloid burden in APPswe/PS1dE9 mice , 2009, Neuroscience.

[28]  S. Hébert,et al.  Hypothermia-induced hyperphosphorylation: a new model to study tau kinase inhibitors , 2012, Scientific Reports.

[29]  P. Maher.  Modulation of multiple pathways involved in the maintenance of neuronal function during aging by fisetin , 2009, Genes & Nutrition.

[30]  S. Paul,et al.  Tau pathogenesis is promoted by Aβ1-42 but not Aβ1-40 , 2014, Molecular Neurodegeneration.

[31]  D. Woodruff-Pak,et al.  Animal models of Alzheimer's disease: therapeutic implications. , 2008, Journal of Alzheimer's disease : JAD.

[32]  Hélène Marie,et al.  Genetic Approaches to Investigate the Role of CREB in Neuronal Plasticity and Memory , 2011, Molecular Neurobiology.

[33]  R. Malinow,et al.  Postsynaptic Density 95 controls AMPA Receptor Incorporation during Long-Term Potentiation and Experience-Driven Synaptic Plasticity , 2004, The Journal of Neuroscience.

[34]  P. Cohen,et al.  Inhibition of glycogen synthase kinase-3 by insulin mediated by protein kinase B , 1995, Nature.

[35]  Dr David Vauzour.  Effect of flavonoids on learning, memory and neurocognitive performance: relevance and potential implications for Alzheimer's disease pathophysiology. , 2014, Journal of the science of food and agriculture.

[36]  Qi Wu,et al.  Curcumin inhibits Aβ-induced microglial inflammatory responses in vitro: Involvement of ERK1/2 and p38 signaling pathways , 2015, Neuroscience Letters.

[37]  Mengjie Xu,et al.  Schisandrin C Ameliorates Learning and Memory Deficits by Aβ1–42‐induced Oxidative Stress and Neurotoxicity in Mice , 2015, Phytotherapy research : PTR.

[38]  Ling-Yun Wu,et al.  Fisetin alleviates early brain injury following experimental subarachnoid hemorrhage in rats possibly by suppressing TLR 4/NF-κB signaling pathway , 2015, Brain Research.

[39]  P. Maher,et al.  Modulation of p25 and inflammatory pathways by fisetin maintains cognitive function in Alzheimer’s disease transgenic mice , 2013, Aging cell.

[40]  F. LaFerla,et al.  Extracellular deposition of beta-amyloid upon p53-dependent neuronal cell death in transgenic mice. , 1996, The Journal of clinical investigation.

[41]  R. Cunha,et al.  Adenosine A2A Receptor Blockade Prevents Synaptotoxicity and Memory Dysfunction Caused by β-Amyloid Peptides via p38 Mitogen-Activated Protein Kinase Pathway , 2009, The Journal of Neuroscience.

[42]  T. Pozzan,et al.  Aβ42 oligomers selectively disrupt neuronal calcium release , 2015, Neurobiology of Aging.

[43]  G. Juhász,et al.  Amyloid- (cid:1) 1 - 42 Disrupts Synaptic Plasticity by Altering Glutamate Recycling at the Synapse , 2015 .

[44]  G. Sudhandiran,et al.  Dietary flavonoid fisetin regulates aluminium chloride-induced neuronal apoptosis in cortex and hippocampus of mice brain. , 2015, The Journal of nutritional biochemistry.

[45]  Kumiko Sakai-Kato,et al.  Structural requirements for the flavonoid fisetin in inhibiting fibril formation of amyloid β protein , 2008, Neuroscience Letters.

[46]  C. Arias,et al.  Inhibition of Wnt and PI3K Signaling Modulates GSK-3β Activity and Induces Morphological Changes in Cortical Neurons: Role of Tau Phosphorylation , 2008, Neurochemical Research.

[47]  D. Ulrich.  Amyloid-β Impairs Synaptic Inhibition via GABAA Receptor Endocytosis , 2015, The Journal of Neuroscience.

[48]  H. Mukhtar,et al.  Fisetin: a dietary antioxidant for health promotion. , 2013, Antioxidants & redox signaling.

[49]  J. Midiwo,et al.  Antioxidant Activity, Cellular Bioavailability, and Iron and Calcium Management of Neuroprotective and Nonneuroprotective Flavones , 2014, Neurotoxicity Research.

[50]  Y. Auberson,et al.  Amyloid beta peptide 1-42 disturbs intracellular calcium homeostasis through activation of GluN2B-containing N-methyl-d-aspartate receptors in cortical cultures. , 2012, Cell Calcium.

[51]  J. Pozueta,et al.  Synaptic changes in Alzheimer’s disease and its models , 2013, Neuroscience.

[52]  L. Buée,et al.  Neurotoxicity and Memory Deficits Induced by Soluble Low-Molecular-Weight Amyloid-β1–42 Oligomers Are Revealed In Vivo by Using a Novel Animal Model , 2012, The Journal of Neuroscience.

[53]  R. Maccioni,et al.  Neuroinflammation: implications for the pathogenesis and molecular diagnosis of Alzheimer's disease. , 2008, Archives of medical research.

[54]  J. Strosznajder,et al.  Effect of amyloid beta peptide on poly(ADP-ribose) polymerase activity in adult and aged rat hippocampus. , 2000, Acta biochimica Polonica.

[55]  R. Malinow,et al.  AMPAR Removal Underlies Aβ-Induced Synaptic Depression and Dendritic Spine Loss , 2006, Neuron.

[56]  M. Kim,et al.  Melatonin ameliorates amyloid beta‐induced memory deficits, tau hyperphosphorylation and neurodegeneration via PI3/Akt/GSk3β pathway in the mouse hippocampus , 2015, Journal of pineal research.

[57]  Ning Li,et al.  FLZ Alleviates the Memory Deficits in Transgenic Mouse Model of Alzheimer’s Disease via Decreasing Beta-Amyloid Production and Tau Hyperphosphorylation , 2013, PloS one.

[58]  K. Iqbal,et al.  Truncation and activation of GSK-3β by calpain I: a molecular mechanism links to tau hyperphosphorylation in Alzheimer's disease , 2015, Scientific Reports.

[59]  W. Klein,et al.  Amyloid β oligomers in Alzheimer’s disease pathogenesis, treatment, and diagnosis , 2015, Acta Neuropathologica.

[60]  D. Ruano,et al.  Age-dependent Accumulation of Soluble Amyloid β (Aβ) Oligomers Reverses the Neuroprotective Effect of Soluble Amyloid Precursor Protein-α (sAPPα) by Modulating Phosphatidylinositol 3-Kinase (PI3K)/Akt-GSK-3β Pathway in Alzheimer Mouse Model* , 2011, The Journal of Biological Chemistry.

[61]  C. V. von Arnim,et al.  Biochemical stages of amyloid-β peptide aggregation and accumulation in the human brain and their association with symptomatic and pathologically preclinical Alzheimer's disease. , 2014, Brain : a journal of neurology.

[62]  Sulei Wang,et al.  Esculentoside A suppresses Aβ1–42-induced neuroinflammation by down-regulating MAPKs pathways in vivo , 2015, Neurological research.

[63]  J. Bureš,et al.  beta-Amyloid infusion results in delayed and age-dependent learning deficits without role of inflammation or beta-amyloid deposits. , 2006, Proceedings of the National Academy of Sciences of the United States of America.

[64]  S. Biswas,et al.  The Essential Role of p53-up-regulated Modulator of Apoptosis (Puma) and Its Regulation by FoxO3a Transcription Factor in β-Amyloid-induced Neuron Death* , 2014, The Journal of Biological Chemistry.

[65]  Tony Wyss-Coray,et al.  Inflammation in Neurodegenerative Disease—A Double-Edged Sword , 2002, Neuron.

[66]  Quanfang Huang,et al.  Pratensein attenuates Aβ-induced cognitive deficits in rats: enhancement of synaptic plasticity and cholinergic function. , 2015, Fitoterapia.

[67]  S. Biswas,et al.  The regulation of p53 up‐regulated modulator of apoptosis by JNK/c‐Jun pathway in β‐amyloid‐induced neuron death , 2015, Journal of neurochemistry.

[68]  J. Purcell,et al.  ERK activation by the polyphenols fisetin and resveratrol provides neuroprotection in multiple models of Huntington's disease. , 2011, Human molecular genetics.

[69]  G. Sudhandiran,et al.  Fisetin Enhances Behavioral Performances and Attenuates Reactive Gliosis and Inflammation During Aluminum Chloride-Induced Neurotoxicity , 2013, NeuroMolecular Medicine.

[70]  B. Barneda-Zahonero,et al.  Soluble Oligomers of Amyloid-β Peptide Disrupt Membrane Trafficking of α-Amino-3-hydroxy-5-methylisoxazole-4-propionic Acid Receptor Contributing to Early Synapse Dysfunction* , 2011, The Journal of Biological Chemistry.