Fisetin as a Neuroprotective Flavonoid in Alzheimer's Disease; Targeting Bdnf and TAU Pathways

Abstract

Alzheimer's disease (AD) is a progressive neurodegenerative disorder that causes cognitive decline, synaptic dysfunction, neuronal loss, and characteristic pathologies such as Tau hyperphosphorylation and neurofibrillary tangle formation. In addition to amyloid and Tau pathology, impaired brain-derived neurotrophic factor (BDNF) signaling, oxidative stress, and chronic neuroinflammation all play important roles in disease development. Current therapeutic approaches only provide symptomatic alleviation, emphasizing the critical need for diseasemodifying medicines capable of addressing numerous pathogenic pathways. Fisetin, a naturally occurring dietary flavonoid, has received increased interest due to its extensive neuroprotective potential in AD. Preclinical investigations show that fisetin has antioxidant and anti-inflammatory properties while also improving neuronal survival and synaptic plasticity. Fisetin regulates BDNF signaling by increasing BDNF expression and activating downstream pathways such as Trk-B, CREB, PI3K/Akt, and MAPK, so promoting learning and memory processes. Fisetin reduces Tau pathology by suppressing hyperphosphorylation and aggregation. It does this by regulating important kinases such glycogen synthase kinase-3β (GSK-3β), which helps stabilize microtubules and maintain neuronal integrity. Despite convincing preclinical evidence, the clinical translation of fisetin is hampered by issues such as inadequate bioavailability, insufficient human research, and a lack of knowledge of its pharmacokinetics. Future research should focus on enhancing fisetin delivery using innovative formulations, verifying its efficacy in clinical trials, and investigating synergistic effects with existing AD medications. Fisetin stands out as a promising multitarget option for Alzheimer's disease prevention and treatment since it targets both BDNF-mediated neurotrophic support and Tau-associated neurodegenerative pathways.