Scientists manipulate enzyme to counter dementia

People suffering from dementia could eventually benefit from a new understanding of a brain enzyme named protein kinase M zeta (PKMzeta).

By JUDY SIEGEL-ITZKOVICH
People suffering from dementia – and other problems with deteriorating memories – could eventually benefit from a new understanding of a brain enzyme named protein kinase M zeta (PKMzeta).
The Weizmann Institute of Science and New York’s SUNY Downstate Medical Center have successfully manipulated the enzyme in rats to improve memory.
The work was chronicled by Downstate, where Prof. Toss Sacktor, a grantte of the US National Institute of Health’s National Institute of Mental Health, conducts research. The results generated great interest after it was published over the weekend in the journal Science.
By manipulating the enzyme, the team found they could erase long-term memories, and perform the opposite feat: enhance memories that had been erased long ago.
“Our study is the first to demonstrate that, in the context of a functioning brain in a behaving animal, a single molecule, PKMzeta, is both necessary and sufficient for maintaining longterm memory,” Sacktor said.
Unlike other recently discovered approaches to memory enhancement, the PKMzeta mechanism appears to work any time.
It is not dependent on exploiting time-limited windows, when a memory becomes temporarily fragile and changeable – like just after learning and upon retrieval – which may expire as a memory grows older, said Sacktor.
“This pivotal mechanism could become a target for treatments to help manage debilitating emotional memories in anxiety disorders, and for enhancing faltering memories in disorders of aging,” said NIMH Director Dr. Thomas Insel.
In studies going back five years, Dudai and Sacktor showed that even weeks after rats learned to associate a nauseating sensation with saccharin – and shunned the sweet taste – their sweet tooth returned within a couple of hours after receiving a chemical that blocked the enzyme PKMzeta in the brain’s outer mantle, where long-term memories are stored.
In the new study, they paired genetic engineering with the same aversive learning model to both confirm the earlier studies, and demonstrate that by increasing PKMzeta, the opposite effect transpired.
They harnessed a virus to infect the neocortex with the PKMzeta gene, resulting in overexpression of the enzyme and memory enhancement.
Conversely, introducing a mutant inactive form of the enzyme, that replaced the naturally occurring one, erased the memory – much as the chemical blocker did.
These effects applied generally to multiple memories stored in the targeted brain area – raising questions about how specific memories might be targeted in future therapeutic applications.
Indeed, the researchers turned up a clue that may hold the beginning of an answer.
“One explanation of the memory enhancement is that PKMzeta might go to some synapses, or connections between brain cells, and not others,” Sacktor said. “Overexpressed PKMzeta may be selectively captured by molecular tags that mark just those brain connections where it’s needed – likely synapses that were holding the memory from the training.”