Alzheimer’s disease is marked by increasing dementia as neurodegeneration progresses, beginning with the loss of connections between neurons (synapses), which are critical to memory storage.
Numerous labs have discovered that inhibiting a class of enzymes called HDACs [histone deacetylases] can rescue memory. HDACs are a family of enzymes that act like on/off buttons for genes. Scientists know there are five classes of HDAC enzymes.
It was not known which HDACs offer the best target for treating memory disorders, however. Most research teams have focused on developing inhibitors that hit only certain forms of HDACs, in order to minimize side effects, since these enzymes do play crucial roles in the healthy body.
Now, scientists at Scripps have shown that attacking more than one form of HDAC could be a viable strategy.
“We wanted to find out which inhibitors were the most selective and the most effective in restoring memory function,” study author Courtney Miller explained. The key to memory restoration seems to be the growth of new synapses, which required the simultaneous inhibitor of multiple HDACs.
The scientists had used three inhibitors of HDAC from the Repligen Corporation based in Massachusetts. These compounds are licensed to Biomarin, who are extending preclinical studies.
“We compared compounds that hit a variety of combinations of HDACs 1, 2 and 3. It turns out that synaptogenesis was most effective when all three were simultaneously inhibited and that memory was rescued in a mouse model of Alzheimer’s disease [AD],” said Miller.
“Further, we found that inhibiting HDAC3 alone was insufficient to rescue memory in the AD mice and did not lead to the formation of new [neural] spines in the brain. This was somewhat of a surprise because HDAC3 has been shown to have memory enhancing effects in healthy, wild type mice.
“To us, this points to the creation of new spines as a key to HDAC inhibition’s memory rescuing effects in the face of neurodegeneration.”
The simultaneous inhibition of HDAC1, 2, and 3 with the Repligen inhibitor RGFP963 also led to better synapse function in cultured neurons. The Scripps scientists concluded that simultaneous inhibition of all three is a promising therapeutic avenue for memory rescue in Alzheimer’s.
The study used a mouse model of Alzheimer’s disease; no memory boost was observed in healthy animals pretreated with HDAC inhibitors, “suggesting that increasing synapse efficacy above baseline levels in a healthy brain does not necessarily lead to memory enhancement,” the study notes.
“A direct connection between synaptogenesis and memory rescue in Alzheimer’s needs to be demonstrated,” Miller added.
“Our hope is that Biomarin is interested in further developing these compounds for AD. In the meantime, we are exploring new avenues for driving synaptogenesis in the brain.”