Abstract
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 Aβ is considered to be the initial event. Thus, prevention of Aβ production would be an ideal strategy for the treatment or prevention of AD. Aβ is produced via the proteolytic cleavage of its precursor protein, APP (amyloid precursor protein), by two different enzymes, β and γ-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 γ-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 Aβ 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 Aβ 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.
Highlights
Alzheimer Disease (AD) is the most frequently observed neurodegenerative disorder, in Japan and other advanced countries [1,2,3]
Screening of plant extracts that inhibit Ab production We previously developed an assay in which proteolytic activities directed at membrane proteins can be converted to a transcriptional activity readout [24]
The ‘‘amyloid hypothesis’’ predicts that reduction of Ab production or accumulation would be an effective strategy for the treatment or prevention of AD
Summary
Alzheimer Disease (AD) is the most frequently observed neurodegenerative disorder, in Japan and other advanced countries [1,2,3]. Several inhibitors for cholinesterase, e.g. donepezil (Aricept), are available for mitigating clinical phenotypes, but are not able to inhibit the progression of neuronal cell death; the long-term prognosis has not appreciably changed [4,5]. In the brains of AD patients, two major pathologies have been observed, namely Ab depositions and neurofibrillary tangles [1]. Neurofibrillary tangles are composed of hyper-phosphorylated tau proteins [9]. Several pathological mechanisms have been proposed for AD. Most widely accepted, is the ‘‘amyloid hypothesis’’, which posits that accumulation/deposition of Ab is the initial event, which in turn induces neurofibrillary tangles, leading to neuronal dysfunction and neuronal cell death [10,11]
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