In the brains of Alzheimer’s patients, many of the genes required to form new memories are shut down by a genetic blockade, contributing to the cognitive decline seen in those patients.
MIT researchers have now shown that they can reverse that memory loss in mice by interfering with the enzyme that forms the blockade. The enzyme, known as HDAC2, turns genes off by condensing them so tightly that they can’t be expressed.
For several years, scientists and pharmaceutical companies have been trying to develop drugs that block this enzyme, but most of these drugs also block other members of the HDAC family, which can lead to toxic side effects. The MIT team has now found a way to precisely target HDAC2, by blocking its interaction with a binding partner called Sp3.
“This is exciting because for the first time we have found a specific mechanism by which HDAC2 regulates synaptic gene expression,” says Li-Huei Tsai, director of MIT’s Picower Institute for Learning and Memory and the study’s senior author.
Blocking that mechanism could offer a new way to treat memory loss in Alzheimer’s patients. In this study, the researchers used a large protein fragment to interfere with HDAC-2, but they plan to seek smaller molecules that would be easier to deploy as drugs.
Picower Institute postdocs Hidekuni Yamakawa, Jemmie Cheng, and Jay Penney are the lead authors of the study, which appears in the Aug. 8 edition of Cell Reports.