
Modulation of p25 and inflammatory pathways by fisetin maintains cognitive function in A lzheimer's disease transgenic mice
Author(s) -
Currais Antonio,
Prior Marguerite,
Dargusch Richard,
Armando Aaron,
Ehren Jennifer,
Schubert David,
Quehenberger Oswald,
Maher Pamela
Publication year - 2014
Publication title -
aging cell
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 3.103
H-Index - 140
eISSN - 1474-9726
pISSN - 1474-9718
DOI - 10.1111/acel.12185
Subject(s) - fisetin , neurodegeneration , genetically modified mouse , biology , neuroinflammation , transgene , neuroscience , microbiology and biotechnology , alzheimer's disease , disease , inflammation , immunology , medicine , biochemistry , flavonoid , gene , antioxidant
Summary 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 APP swe/ PS 1d E 9 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 ( C dk5) activator p35 cleavage product, p25, in both control and AD brains. Elevated levels of p25 relative to p35 cause dysregulation of C dk5 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 .