Alzheimer disease is a progressive neurodegenerative disorder that impairs memory and mental function. It is the most common form of dementia, accounting for 60–70% of cases, and its prevalence is increasing worldwide, a trend that is expected to continue for the next few decades. Memory loss in Alzheimer disease is driven by the loss of synapses. Previous research has shown that memory can be partially restored in animal models of Alzheimer disease by inhibiting a family of enzymes called histone deacetylases (HDACs), which are involved in transcriptional control of gene expression. HDACs have many roles in the body, however, and manipulating them to improve memory might have unwanted effects on other systems. To minimize these off-target effects, some neuroscientists have suggested refining HDAC inhibition to focus on specific HDAC isoforms. But it is not known which isoforms have the greatest potential to affect memory nor how selective HDAC inhibition might affect synapse formation or function.

Researchers at The Scripps Research Institute (Jupiter, FL) led a study to address these questions. They tested the effects of HDAC inhibitors with different isoform selectivity on synaptogenesis and memory. “We wanted to find out which inhibitors were... the most effective in restoring memory function,” said Courtney Miller in a press release. Miller is senior author on the paper describing the study (Neuropsychopharmacol. doi:10.1038/npp.2015.93; published online 22 April 2015).

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Simultaneous inhibition of HDAC-1, HDAC-2 and HDAC-3 was most effective at stimulating synaptogenesis, whereas selective inhibition of HDAC-1 and HDAC-2 together or of HDAC-3 alone induced much less, even minimal, synapse formation. First author on the paper Gavin Rumbaugh observed, “We found evidence that better synapse growth was associated with less specific inhibition of... HDACs.” Spinogenesis similarly responded more robustly to inhibition of three HDAC isoforms than to selective inhibition of HDAC-3. And in a transgenic mouse model of Alzheimer disease, simultaneous inhibition of HDAC-1, HDAC-2 and HDAC-3 restored memory whereas selective inhibition of HDAC-3 did not.

Taken together, the results indicate that “the key to memory restoration was... synaptogenesis, which required simultaneous inhibition of multiple HDACs,” explained Miller. The findings suggest that simultaneous inhibition of HDAC-1, HDAC-2 and HDAC-3 holds promise as a strategy to restore memory in Alzheimer disease, although more studies are needed to find a balance between treatment efficacy and off-target effects associated with HDAC inhibition.