Scientists unclog genetic brain blockade in mice with Alzheimer's
Researchers at MIT have uncovered a new potential treatment for reversing memory loss of Alzheimer's sufferers. The technique targets an enzyme known as HDAC2, which blocks genes vital to memory formation in Alzheimer's patients, and so far it has shown promise in tests in mice.
HDAC2 has long been a suspect in this particular crime, since its levels are usually elevated in Alzheimer's patients. But singling it out for treatment hasn't been easy: it's part of a large family of HDAC enzymes that perform key functions. Other HDAC inhibitors also affect the closely-related HDAC1, which can trigger dangerous side effects by interfering with the production of red and white blood cells. The MIT study however is the first to only block HDAC2.
"This is exciting because for the first time we have found a specific mechanism by which HDAC2 regulates synaptic gene expression," says Li-Huei Tsai, senior author of the study. "We think that HDAC2 serves as a master regulator of memory gene expression, and during Alzheimer's disease it's elevated so it causes an epigenetic blockade of the expression of those memory genes. If we can remove the blockade by inhibiting HDAC2 activity or reducing HDAC2 levels, then we can remove the blockade and restore expression of all these genes necessary for learning and memory."
To narrow their sights on HDAC2, the researchers studied postmortem brain samples from people who didn't have Alzheimer's. The samples included 28 brains with high levels of HDAC2 and 35 with low levels, and the team analyzed them in terms of their gene expression data. That resulted in a list of about 2,000 genes that seemed to be related to different HDAC2 levels.
That list was shortened based on further testing and the scientists' existing understanding of the genes, until only one remained. A gene called Sp3 seemed to be a crucial part of how HDAC2 was blocking memory formation, and when it was cross-examined with brain samples from Alzheimer's patients, a nearly perfect correlation was found between HDAC2 levels and Sp3.
With the connection uncovered, the team then located which part of the HDAC2 protein binds to Sp3, and using Alzheimer's-stricken mice, they created neurons that produced too much of that section. In doing so, the Sp3 gene was kept busy and all but deactivated, which in turn effectively unclogged the animals' memory-forming pathways. Better yet, it did so without affecting HDAC1 or its duties in cell proliferation.
"This therapeutic approach is specific to the action of HDAC2 and does not affect other HDACs, such as the close homologue HDAC1," says Andre Fischer, a German professor who wasn't involved in the study. "The data raise hopes that therapeutic strategies targeting Sp3 or the interaction of Sp3 with HDAC2 may overcome the issue of lacking specificity of HDAC2 inhibitors."
As it stands, the HDAC2 protein fragment is too big to use as a drug in human trials, but the researchers plan to investigate other ways to translate the technique. That includes searching for smaller sections of the same protein, other chemical compounds that would do the same job, or other genes that might be related.
The research was published in the journal Cell Reports.