title: 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 Aβ1-42mouse 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 Aβ1-42injection 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 Aβ1-42injections 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.
authors.affiliation: Department of Biology and Applied Life Science (BK 21), College of Natural Sciences (RINS), Gyeongsang National University, Jinju, 660-701, Republic of Korea.
authors.forename: Ashfaq
authors.initials: A
authors.lastname: Ahmad
authors.affiliation: Department of Biology and Applied Life Science (BK 21), College of Natural Sciences (RINS), Gyeongsang National University, Jinju, 660-701, Republic of Korea.
authors.forename: Tahir
authors.initials: T
authors.lastname: Ali
authors.affiliation: School of Medicine, Case Western Reserve University, Cleveland, Ohio, USA.
authors.forename: Hyun Young
authors.initials: HY
authors.lastname: Park
authors.affiliation: Department of Biology and Applied Life Science (BK 21), College of Natural Sciences (RINS), Gyeongsang National University, Jinju, 660-701, Republic of Korea.
authors.forename: Haroon
authors.initials: H
authors.lastname: Badshah
authors.affiliation: Department of Biology and Applied Life Science (BK 21), College of Natural Sciences (RINS), Gyeongsang National University, Jinju, 660-701, Republic of Korea.
authors.forename: Shafiq Ur
authors.initials: SU
authors.lastname: Rehman
authors.affiliation: Department of Biology and Applied Life Science (BK 21), College of Natural Sciences (RINS), Gyeongsang National University, Jinju, 660-701, Republic of Korea. mokim@gnu.ac.kr.
authors.forename: Myeong Ok
authors.initials: MO
authors.lastname: Kim
mesh_terms: D016229:Amyloid beta-Peptides / Q000378:metabolism / Q000494:pharmacology*; D000818:Animals; D003071:Cognition / Q000187:drug effects*; D060825:Cognitive Dysfunction / Q000188:drug therapy; D004195:Disease Models, Animal; D005419:Flavonoids / Q000494:pharmacology*; D044948:Flavonols; D008297:Male; D008810:Mice, Inbred C57BL; D009422:Nervous System Diseases / Q000188:drug therapy* / Q000378:metabolism; D009473:Neuronal Plasticity / Q000187:drug effects; D009474:Neurons / Q000378:metabolism; D018696:Neuroprotective Agents / Q000494:pharmacology*
chemical_list: D016229:Amyloid beta-Peptides; D005419:Flavonoids; D044948:Flavonols; D018696:Neuroprotective Agents; C017875:fisetin
keywords: Alzheimer’s disease; Beta-amyloid (Aβ1–42); Fisetin; Neurodegeneration; Neuroinflammation; Synaptic dysfunctions