BT2 as a novel therapeutic compound for Alzheimer’s disease



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Alzheimer’s disease (AD) is estimated to be the sixth leading cause of death in the U.S. without any effective treatment strategies. Our lab has shown that elevated branched-chain amino acids (BCAAs) may play a causal role in the progression of AD-related pathology. Our pilot data revealed that 8 weeks of dietary BCAA restriction in AD mice alleviated AD-related brain pathology and improved cognitive function. Although we observed beneficial effects from dietary intervention, this approach is practically challenging because BCAAs are found in a wide variety of foods. This prompted us to test the effects of pharmacologically lowering BCAAs in AD mice using BT2, a small molecule that increases BCAA breakdown. First, we used cognitively impaired APP/PS1 and wildtype (WT) mice to test the effects of BT2 on cognitive function, AD-related pathology and associated metabolic dysfunction. We found that BT2 did not alleviate cognitive impairment or AD-related pathology in late-stage APP/PS1 mice. We then used cognitively intact 6-week-old 5xFAD mice and wildtype (WT) mice to test the effects of BT2 on early AD-related brain pathology. BT2 lowered plasma BCAAs as expected, normalized 5xFAD FBG levels to WTs, restored key neurotransmitters (NTs) associated with memory and learning functions, and reduced GSK3β which may help minimize the formation of neurofibrillary tangles (NFTs). Next, we wanted to test if BT2 prevents and/or delays the progression of cognitive decline or AD-related pathology if administered in the early stages of AD development before the onset of cognitive impairment in 5xFAD mice. At 17 weeks of age, the 5xFAD BT2 group displayed higher cognition compared to 5xFAD controls based on spontaneous alternation during Y Maze and restored key NTs. Our findings suggest that early intervention with BT2 has therapeutic effects on AD-related pathology and cognitive impairment in 5xFAD mice. Further research is needed to test different dosing, durations, sex, and route of administration.



Alzheimer's Disease, therapeutics, mice, neurodegenerative, branched-chain amino acids (BCAAs)