An overactive enzyme called HDAC2 may be at the core of memory decline, according to HHMI investigator Li-Huei Tsai, whose lab team showed that blocking the enzyme restores memory in mice with Alzheimer’s disease.
HDAC2 switches off genes implicated in learning and memory. When the enzyme was overexpressed in mice, memory function dropped and there was a significant loss of synapses—the information transfer stations between brain neurons. When the researchers reduced HDAC2 in neurons of mice exhibiting Alzheimer’s disease, they found a dramatic increase in the number of active synapses. After only four weeks, the HDAC2-blocked mice were indistinguishable from healthy mice in memory tests.
The researchers, whose work was published February 29, 2012, in Nature, also discovered what might put HDAC2 into overdrive. Two known Alzheimer’s indicators, the protein amyloid-b and oxidative stress—an excess of a reactive form of oxygen—can activate the protein glucocorticoid receptor 1, which in turn switches on rampant production of HDAC2.
Tsai, who is at the Massachusetts Institute of Technology, is eager to see whether blocking HDAC2 is effective in humans. “We need to test this hypothesis in humans to see whether this concept holds up,” she says. “While all the data look very promising in animal models, human studies are a completely different ball game.”