Long-Term Oral Administration of Hop Flower Extracts Mitigates Alzheimer Phenotypes in Mice

Coincident with the expanding population of aged people, the incidence of Alzheimer disease (AD) is rapidly increasing in most advanced countries. At present, no effective prophylactics are available. Among several pathological mechanisms proposed for AD, the amyloid hypothesis has been most widely accepted, in which accumulation or deposition of A beta is considered to be the initial event. Thus, prevention of A beta production would be an ideal strategy for the treatment or prevention of AD. A beta is produced via the proteolytic cleavage of its precursor protein, APP (amyloid precursor protein), by two different enzymes, beta and gamma-secretases. Indeed, inhibitors against either or both enzymes have been developed and tested for clinical efficacy. Based on the amyloid hypothesis, we developed a luciferase-based screening method to monitor gamma-secretase activity, screened more than 1,600 plant extracts, most of which have long been used in Chinese medicine, and observed that Hop extracts significantly inhibit A beta production in cultured cells. A major component of the inhibitory activity was purified, and its chemical identity was determined by NMR to be Garcinielliptone HC. In vivo, oral administration of Hop extracts to AD model mice decreased A beta depositions in the cerebral cortex of the parietal lobe, hippocampus, and artery walls (amyloid angiopathy) in the brains. In a Morris water maze test, AD model mice that had daily consumed Hop extracts in their drinking water showed significant mitigation of memory impairment at ages of 9 and 12 months. Moreover, in the open field test oral administration of Hop extracts also prevented an emotional disturbance that appeared in the AD mice at 18 months. Despite lifelong consumption of Hop extracts, no deleterious side effects were observed at any age. These results support the amyloid hypothesis, and indicate that Hop extract is a promising candidate for an effective prophylactic for AD.