Modulation of p25 and inflammatory pathways by fisetin maintains cognitive function in Alzheimer's disease transgenic mice

This Salk Institute study tested a long-shot idea for Alzheimer's disease: since the disease disrupts many different biological systems at once, a single-target drug may not be enough, so the researchers looked for a naturally occurring molecule, fisetin, that touches several of the pathways implicated in Alzheimer's.

Mice genetically engineered to develop Alzheimer's-like brain changes were given oral fisetin continuously from 3 to 12 months of age, spanning the period when these mice normally start to develop learning and memory problems. The fisetin-treated Alzheimer's mice did not develop the learning and memory deficits seen in untreated Alzheimer's mice.

Looking under the hood, fisetin increased activity of the memory-linked ERK signalling pathway and reduced a marker of oxidative protein damage. It also lowered the brain levels of p25, a toxic breakdown product that, when it builds up, overactivates an enzyme (Cdk5) linked to brain inflammation and nerve cell damage in Alzheimer's disease.

Fisetin's effects extended to broader inflammatory chemistry in the brain (eicosanoid, or lipid-signalling, changes) and helped preserve markers of healthy nerve-cell connections (synaptic function), tying together an antioxidant, anti-inflammatory and neuroprotective story in one genetically-defined Alzheimer's model.

This is a well-regarded mechanistic mouse paper for fisetin's neuroprotective reputation, but it used a specific, aggressive amyloid/presenilin transgenic mouse model dosed continuously from a young age - it does not establish that fisetin, taken as a supplement later in life, would prevent or treat Alzheimer's disease in people.