Molecular Pathogenesis, Treatment Strategies and Animal Models of Alzheimer's Disease

Senile plaques and neurofilament tangles are the hallmarks of Alzheimer’s disease (Aβ). Amyloid β protein (Aβ), the major protein component of senile plaques, has been suggested to play an important role in the pathogenesis of AD. Aβ is proteolytically derived from amyloid precursor protein, which is widely expressed throughout the brain. Multiple lines of evidence have demonstrated that fibril Aβ participates in the induction of neuronal death and neuritic changes. The neurotoxic effects of Aβ may be mediated by perturbation of calcium homeostasis and production off reactive oxygen species (ROS). Several agents are neuroprotective in vitro by targeting specific pathways responsible for Aβ-induced toxicity. These agents include antioxidants, free radical scavengers and caspase inhibitors. Flavonoids, the so-called phytoestrogens, display both antioxidative and antiproliferative activities. We have demonstrated that the neuronal apoptosis induced by Aβ is inhibited by kaempferol, and to a lesser extent by apigenin. Kaempferol exhibits antioxidative activity and decreases the ROS accumulation induced by Aβ, whereas apigenin only shows a marginal effect on ROS levels. These results indicate that blockade of the caspase cascade is responsible for the neuroprotective effects of phytoestrogens on Aβ-mediated neurotoxicity. Inhiibition of the caspase cascade in combination with antioxidative activity may further reduce Aβ-mediated neurotoxicity. Some animal models have been used to study AD. A transgenic mouse, Tg2576, has been established by over-expressing the mutated human Aβ precursor protein. The correlative appearance of behavioral, biochemical, and pathological abnormalities reminiscent of Alzheimer’s disease in these transgenic mice suggests new opportunities for exploring the pathophysiology and neurobiology of this disease.

並列關鍵字

Alzheimer's disease ； Amyloid β ； Neurotoxicity ； Animal model

國際替代計量

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