Targeting a brain protein to preserve memory

When people age, certain circuits in the brain’s hippocampus—the region that generates and stores memories—become hyperactive. That may be why memories become jumbled, many scientists believe. And it’s not just age that causes those circuits to malfunction. People with post-traumatic stress disorder (PTSD) also lose the ability to remember specific details over time.

Now scientists at the Massachusetts General Hospital Center for Regenerative Medicine and the Harvard Stem Cell Institute believe they’ve identified a brain protein that exacerbates memory loss with age or PTSD. It’s called abLIM3, and the team showed that if they manipulated levels of the protein in mice, they could preserve the specificity of memories over time.

They started by training the animals to associate a mild but unpleasant foot shock with being placed a particular environment, such as a darkly covered box. The animals eventually started freezing in anticipation anytime they were put in that box. But two weeks later, they froze whenever they were put in an unfamiliar environment—even if it was a completely different box with lightly covered walls. That indicated that they remembered the shock, but not specific details of the environment associated with it.

Then the scientists tried lowering levels of abLIM3 in cells of the hippocampus called dentate gyrus, which are directly involved in memory formation. That allowed the mice to retain the specificity of their memories. So two weeks after learning to associate foot shocks with darkly covered boxes, they only froze when put into those boxes.

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The Harvard researchers were encouraged by their findings, published in the journal Nature Medicine, particularly because previous studies had shown increased levels of abLIM3 in elderly people with memory loss. They’re now “actively pursuing” targeting abLIM3 expression in human trials, said Amar Sahay, Ph.D., associate professor of psychiatry at Harvard Medical School and principal faculty of the Harvard Stem Cell Institute, in a statement.

Targeting wayward brain proteins has been the primary strategy in Alzheimer’s research, with most efforts in Big Pharma focusing on tau and beta-amyloid—proteins associated with the formation of brain plaques believed to cause memory loss. The so-called amyloid hypothesis in Alzheimer’s has come under question, though, most recently with the failure of Merck’s drug inhibiting BACE1, an enzyme believed to promote the formation of amyloid plaques.

So several early-stage programs are zeroing in on alternate strategies for combating brain plaques. Earlier this month, for example, scientists at the University of Washington reported that they used pluripotent stem cells derived from the skin of Alzheimer’s patients to test a new compound that reduces the production of amyloid-beta and tau.

The Harvard-led team believes their strategy of lowering abLIM3 levels should be investigated, not only in age-related memory loss but also in PTSD. "Since overgeneralization of traumatic memories is a hallmark of PTSD, we are also keen to assess abLIM3 levels in patients with PTSD and investigate whether reducing abLIM3 expression could prevent the activation of traumatic memories," Sahay said.