title: Modulation of p25 and inflammatory pathways by fisetin maintains cognitive function in Alzheimer's disease transgenic mice.
abstract: Alzheimer's disease (AD) is the most common type of dementia. It is the only one of the top ten causes of death in the USA for which prevention strategies have not been developed. Although AD has traditionally been associated with the deposition of amyloid β plaques and tau tangles, it is becoming increasingly clear that it involves disruptions in multiple cellular systems. Therefore, it is unlikely that hitting a single target will result in significant benefits to patients with AD. An alternative approach is to identify molecules that have multiple biological activities that are relevant to the disease. Fisetin is a small, orally active molecule which can act on many of the target pathways implicated in AD. We show here that oral administration of fisetin to APPswe/PS1dE9 double transgenic AD mice from 3 to 12 months of age prevents the development of learning and memory deficits. This correlates with an increase in ERK phosphorylation along with a decrease in protein carbonylation, a marker of oxidative stress. Importantly, fisetin also reduces the levels of the cyclin-dependent kinase 5 (Cdk5) activator p35 cleavage product, p25, in both control and AD brains. Elevated levels of p25 relative to p35 cause dysregulation of Cdk5 activity leading to neuroinflammation and neurodegeneration. These fisetin-dependent changes correlate with additional anti-inflammatory effects, including alterations in global eicosanoid synthesis, and the maintenance of markers of synaptic function in the AD mice. Together, these results suggest that fisetin may provide a new approach to the treatment of AD.
authors.affiliation: The Salk Institute for Biological Studies, 10010 N. Torrey Pines Road, La Jolla, CA, 92037, USA.
authors.forename: Antonio
authors.initials: A
authors.lastname: Currais
authors.forename: Marguerite
authors.initials: M
authors.lastname: Prior
authors.forename: Richard
authors.initials: R
authors.lastname: Dargusch
authors.forename: Aaron
authors.initials: A
authors.lastname: Armando
authors.forename: Jennifer
authors.initials: J
authors.lastname: Ehren
authors.forename: David
authors.initials: D
authors.lastname: Schubert
authors.forename: Oswald
authors.initials: O
authors.lastname: Quehenberger
authors.forename: Pamela
authors.initials: P
authors.lastname: Maher
mesh_terms: D000544:Alzheimer Disease / Q000150:complications / Q000378:metabolism / Q000473:pathology* / Q000503:physiopathology*; D000818:Animals; D016718:Arachidonic Acid / Q000378:metabolism; D001253:Astrocytes / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D015415:Biomarkers / Q000378:metabolism; D003071:Cognition / Q000187:drug effects*; D004281:Docosahexaenoic Acids / Q000378:metabolism; D004789:Enzyme Activation / Q000187:drug effects; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D005419:Flavonoids / Q000494:pharmacology*; D044948:Flavonols; D006624:Hippocampus / Q000187:drug effects / Q000201:enzymology / Q000473:pathology; D006801:Humans; D007249:Inflammation / Q000150:complications / Q000378:metabolism / Q000473:pathology* / Q000503:physiopathology; D008568:Memory / Q000187:drug effects; D051379:Mice; D008822:Mice, Transgenic; D008954:Models, Biological; D009419:Nerve Tissue Proteins / Q000378:metabolism*; D018384:Oxidative Stress / Q000187:drug effects; D010770:Phosphotransferases; D050050:Protein Carbonylation / Q000187:drug effects; D015398:Signal Transduction / Q000187:drug effects; D051193:Toll-Like Receptors / Q000378:metabolism
chemical_list: D015415:Biomarkers; C492236:Cdk5r1 protein, mouse; D005419:Flavonoids; D044948:Flavonols; D009419:Nerve Tissue Proteins; D051193:Toll-Like Receptors; D004281:Docosahexaenoic Acids; D016718:Arachidonic Acid; D010770:Phosphotransferases; D048049:Extracellular Signal-Regulated MAP Kinases; C017875:fisetin
keywords: ERK; astrogliosis; eicosanoid; lipoxygenase; oxidative stress; prostaglandin