Alzheimer’s Trial Failures May Be Due to Compound That Promoted Amyloid Buildup, Study Says

Alzheimer’s Trial Failures May Be Due to Compound That Promoted Amyloid Buildup, Study Says
Researchers may have discovered the reason certain investigational therapies failed in Alzheimer’s disease clinical trials — a finding that could lead to new trials with a greater chance of success, according to a study published in the journal Cell Reports. A class of drugs, intended to block an enzyme involved in the production of the Alzheimer’s protein amyloid-beta, were seen to actually increase the amount of the protein inside neurons. The finding may not only explain why such therapies failed to improve Alzheimer’s symptoms, but also why patients in some of more than 50 trials became worse with the treatment. The study, "Semagacestat is a Pseudo-Inhibitor of γ-Secretase," examined such drugs, called gamma-secretase inhibitors. Older data suggested that they reduced the secretion of amyloid beta from neurons — a notion the research team at Osaka University in Japan could confirm. But using a new method, the researchers discovered that a subclass of these drugs, including a compound called semagacestat, did not appear to block gamma-secretase. Rather, a byproduct produced when the gamma-secretase enzyme did its work increased when cells were treated with semagacestat. If the enzyme were truly blocked, such byproducts would be seen in lower levels. To examine what was going on, the team looked inside the neurons and found that the compound, rather than preventing the formation of amyloid-beta, prevented its release from the cells. This led to an accumulation of the protein inside, instead of outside, the neurons. The research
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