Drugs that target hdac2 gene reversed alzheimer's in mice


Drugs that target hdac2 gene reversed alzheimer's in mice

Building on earlier research where mice with symptoms of Alzheimer's disease regained long-term memories and the ability to learn, US researchers have now pinpointed the exact gene involved and shown that drugs that target the gene reverse the effect of Alzheimer's and boost cognitive function in mice.

The study was led by Li-Huei Tsai, Picower Professor of Neuroscience at the Picower Institute for Learning and Memory, Massachusetts Institute of Technology and is published in the 7 May issue of Nature.

Tsai said they think the gene, HDAC2 and its associated protein look like promising targets for treating memory impairments.

"HDAC2 regulates the expression of a plethora of genes implicated in plasticity -- the brain's ability to change in response to experience -- and memory formation," she said.

The gene also appears to make long-lasting changes in how other genes are expressed, which enhances memory by increasing numbers of synapses and altering the structure of neural circuits, explained Tsai.

For the study, Tsai and colleagues used mice bred to have Alzheimer's-like symptoms and treated them with histone deacetylase (HDAC) inhibitors, a class of drug that targets HDACs, which are a group of 11 enzymes that behave like master controllers of gene expression.

Following Alzheimer's-like brain atrophy, the mice appeared to have forgotten tasks they had previously learned.

But after they took HDAC inhibitors, the mice regained their long-term memories and ability to learn new tasks. Also, mice that were genetically engineered to have no HDAC2 genes at all showed enhanced memory formation.

Although they have been around for a while, HDACs are an exciting and fast growing new area of research because of their recently discovered effect on chromatin: the DNA spools in the centre of the nucleus of each cell.

Proteins called histones are the scaffolding around which the DNA spools, and these can be changed through a process called acetylation, which changes the shape and structure of chromatin. HDACs inhibit deacetylation which leads to more acetylation.

Some types of HDAC open up the chromatin structure which is thought to ease gene transcription that would otherwise not take place when the structure is too tightly packed.

Tsai explained that maybe the fact long-term memories can be recovered by increasing histone acetylation is because memories just become inacessible rather than lost in cases of apparent memory "loss".

"These findings are in line with a phenomenon known as 'fluctuating memories,' in which demented patients experience temporary periods of apparent clarity," she added.

Tsai explained that to make best use of HDAC inhibitors you have to know exactly which of the enzymes to target to improve cognitive function.

"We have now identified HDAC2 as the most likely target of the HDAC inhibitors that facilitate synaptic plasticity and memory formation," she added.

This will help researchers to see which mechanisms are involved in memory regulation as a result of chromatin changing shape, and also how physiological and pathological conditions in the central nervous system can indirectly affect gene expression, a process called epigenetic regulation.

HDAC inhibitors as a treatment for neurodegenerative diseases are still only at the experimental stage, although they have been is use for some time in psychiatry and neurology as mood stabilizers and anti-epilectics.

Several HDAC inhibitors are being trialled as a new type of anticancer agent and may enter the pipeline for other diseases in the coming two to four years. They have also shown promising results in mouse models of Huntington's disease.

Tsai said that as far they know, HDAC inhibitors have not been used to treat Alzheimer's disease or dementia.

"But now that we know that inhibiting HDAC2 has the potential to boost synaptic plasticity, synapse formation and memory formation, in the next step, we will develop new HDAC2-selective inhibitors and test their function for human diseases associated with memory impairment to treat neurodegenerative diseases," she said.

"HDAC2 negatively regulates memory formation and synaptic plasticity."

Ji-Song Guan, Stephen J. Haggarty, Emanuela Giacometti, Jan-Hermen Dannenberg, Nadine Joseph, Jun Gao, Thomas J. F. Nieland, Ying Zhou, Xinyu Wang, Ralph Mazitschek, et al.

Nature 459, 55-60 Published online 7 May 2009.

doi:10.1038/nature07925

Additional sources: MIT News.

Reversing Alzheimers gene blockade can restore memory (curezone.ca) (Video Medical And Professional 2020).

Section Issues On Medicine: Disease