Researchers Find an Epigenetic Culprit of Memory Decline

In HHMI, Dr. Li-Huei Tsai and her team have recently published a mouse model study suggesting that Alzheimer’s disease has epigenetic origins:  her team's studies conclude that a single overactive enzyme is responsible for disabling the expression of other proteins required for neuron functionality.

The primarily culprit seems to be protein HDAC2, an enzyme which belongs to the histone deacetylase family.  A well-studied form of gene regulation is histone acetylation, wherein histones which are enrapt with DNA strands are acetylated.  Aceytlation of the lysine groups on histone tails neutralizes their positive charges, causing a relaxation in binding of the histones to their nucleosome partners.  As a result, transcription factors have an easier access to genes in acetylated regions.  An overactive histone deacetylase such as HDAC2, which deacetylates regions of DNA-histone complex,can thus dramatically reduce the expression of  related key genes necessary for the functionality of any biological processes, in this case neuron functionality.

The study suggests that inhibition of HDAC2 in mouse models resulted in control and experimental groups performing uniformly better in cognitive tests as opposed to their uninhibited HDAC2 counterparts.  Also, post-mortem autopsies of mouse models known to have degenerative disease states have elevated levels of HDAC2.  However, the scientists noted that although inhibition of HDAC2 restored neuron functionality, the rate of neuron cell death remained higher in mutants than in wild-type.  Dr. Tsai suggests that inhibition of HDAC2 'wakes up' malfunctioning neurons that would otherwise be operational; HDAc2 regulation, however, seems for now to be unlinked to increased neuron cell death.

Histopathologic image of senile plaques seen in the cerebral cortex of a person with Alzheimer's disease of presenile onset. Silver impregnation.