Alzheimer's disease currently affects 5.3 million Americans – a number due to rise to approximately 14 million by 2050, barring a medical breakthrough that can prevent or cure the disease.
Associate Professor Courtney Miller
A team of scientists from Scripps Florida, led by TSRI Associate Professors Courtney Miller and Gavin Rumbaugh, has uncovered some surprising details of a group of enzymes that have previously shown significant potential in stimulating the growth of brain cells and restoring memory in animal models that mimic Alzheimer's disease.
Previous findings from Drs. Miller and Rumbaugh demonstrated the memory-rescuing potential of inhibiting histone deacetylases (HDACs). HDACs are a family of signaling enzymes that act like molecular switches by silencing gene expression through controlling access to the cell's nuclear cache of tightly compacted DNA. Mutations in HDACs genes have been associated with health problems including cancer, inflammatory and autoimmune diseases, metabolic disorders and loss of memory function.
A number of efforts currently focus on developing "isoform-selective" HDAC inhibitors to limit the potential for unwanted side effects. For example, inhibitors that select only members of Class 1 HDACs such as HDAC 1, -2 or -3. However, the Scripps Florida team wondered if some potential of memory rescue was being lost with this increased selectivity.
To investigate, the researchers used inhibitors initially developed by Professor Joel Gottesfeld, a molecular biologist on TSRI's La Jolla campus, and subsequently by biotech firm Repligen Corporation, to attack more than one form of Class 1 HDAC at the same time in a mouse model of Alzheimer's disease.
"We wanted to find out which inhibitors were the most selective and the most effective in restoring memory function," Dr. Miller said. "We found the key to memory restoration was the growth of new synapses (synaptogenesis), which required simultaneous inhibition of multiple HDACs."
"We found evidence that better synapse growth was associated with less specific inhibition of Class 1 HDACs," Dr. Rumbaugh added. "There was a clear correlation between synapse building – which may lead to improved network power – and memory restoration by the different HDAC inhibitors."
Interestingly, the team also found memory was not enhanced in normal animals by chronic pretreatment with multiple HDAC inhibitors, suggesting a diseased brain responds to these compounds differently than a healthy brain.