Amadorins for Ameliorating Alzheimer's Disease and Related Dementias (ADRD)

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PROJECT SUMMARY Alzheimer’s Disease (AD) and related dementias (ADRD) are recognized as major public health issues that are projected to worsen in the aging U.S. population — the number of people of age 65 and older in the U.S. will reach 88 million by 2050. However, despite intensive efforts, there is an absence of sufficiently effective therapeutic options. Advanced glycation end products (AGE) formation is an established pathogenic factor in AD progression, impacting both amyloid beta and tau. Brains are replete with glucose and ascorbate, both of which are AGE precursors. AGE formation is initiated by the breakdown of glucose adducts on proteins via an oxidative chemical reaction requiring redox metal ion catalysis, and it is known that AD progression leads to brain accumulation of pro-oxidant copper and iron. These AGE accelerants generate toxic free radicals and reactive oxygen species (ROS) that can independently cause neuronal damage. Our hypothesis is that a drug candidate that: (1) is brain penetrant, (2) inhibits AGE formation, and (3) reduces oxidation by redox metal ions will exhibit efficacy in treating AD/ADRD. We advance in this proposal the novel “Amadorin” drug candidate PTG-630, a potent inhibitor of advanced glycation end products (AGEs) that also has the dual potential as an antioxidant due to its binding of redox metal ions, particularly Cu2+. We previously discovered that PTG-630 prevents mild cognitive impairment in diabetic rats and in a transgenic mouse model of AD when treatment was begun at onset of disease. We now propose to evaluate the therapeutic potential of PTG-630 in reversing established cognitive dysfunction and neurodegeneration in multiple animal models of AD, as this is the most likely scenario for clinical use of a therapeutic agent.