The Hong Kong Polytechnic University,
Keywords: Alzheimer’s disease, neuroprotection, dimers, traditional Chinese medicines, disease modifying
Summary:Alzheimer’s disease (AD), a progressive brain disorder that severely destroys memory, has emerged as the third leading cause of death among the elderly worldwide. Although the exact cause of AD remains elusive, accumulating lines of evidence have highlighted that multiple factors including toxic β amyloid (Aβ) oligomers might cause the synaptic and memory impairments in AD pathogenesis. Four acetylcholinesterase (AChE) inhibitors (Cognex®, Aricept®, Exelon® and Reminyl®) and N-Methyl-D-Aspartate receptor (NMDAR) antagonist (Namenda®) have been approved by the Food & Drug Administration USA for the treatment of AD. Unfortunately, the approved anti-AD drugs offer only limited and transient effects, but are unable to effectively slowdown or halt the disease progression. The idea of dimerization itself is a novel concept to modify the existing drugs on market. Over the past decade, with the support of grants from China and Hong Kong and collaborations with Profs. Karl Tsim, Paul Carlier, and Joel Sussman, we have developed three series of Chinese medicine-derived novel anti-AD homo- and hetero-dimers including particularly those derived from huperzine A, a unique anti-Alzheimer’s drug originally discovered from a traditional Chinese medicinal plant. The cost to synthesize these new dimers is much lower than that to isolate huperzine A from the natural plant. These dimers have been demonstrated to provide superior acetylcholinesterase inhibition, uncompetitive moderate N-Methyl-D-aspartate receptor antagonism, neural differentiation and remarkable neuroprotections against various neurotoxins in various in vitro and in vivo models associated with AD. Most encouragingly, our very recent findings revealed that several compounds screened from these Chinese medicine-derived dimers effectively blocked neurototoxicity in Aβ oligomers-treated primary hippocampal neurons, inhibition of long-term potentiation in hippocampal slices, and memory deficits in intrahippocampal Aβ oligomers-injected mice. More than 60 refereed journal papers and 5 patents from US, UK and China, have been thus far resulted from these works. In summary, our novel dimers, through inhibition of AChE, N-methyl-D-aspartate receptor, nitric oxide synthase, and Aβ oligomers concurrently, possesses remarkable neuroprotective activities. More importantly, the synergism between these targets might serve as one of the most effective therapeutic strategies to modify pathological process of AD in addition to improving the cognitive functions for AD.