- An enzyme overproduced in the
brains of Alzheimer's patients creates a blockade that shuts off genes and
causes memory loss
- Inhibiting the enzyme HDAC2 can
reverse memory loss in Alzheimer's. HDAC2 inhibitors can also affect other
members of HDAC
- A new approach has been found to
target HDAC2, by blocking its interaction with a binding partner called
In the brains of
Alzheimer's patients, genes that are required to form new memories are shut
down by a genetic blockade, contributing to cognitive decline. A research team
from the Massachusetts Institute of Technology have found a way to reverse memory
loss by interfering with the enzyme that forms the blockade.
The enzyme that
blocks the genes is known as HDAC2 (Histone Deacetylase 2). HDAC2 turns genes
off by condensing them so tightly that they can't be expressed. Pharmaceutical
companies and scientists have been trying to develop drugs that block the HDAC2
enzyme, but most of these drugs also block other members of the HDAC family,
leading to toxic side effects.
New Way to Treat
Memory Loss in Alzheimer's
method found by the MIT research team targets HDAC2 by blocking its interaction
with a binding partner called Sp3 (Savoia-Pomilio SP.3).
Blocking this mechanism could treat memory loss in Alzheimer's
‘MIT scientists have found a way to target HDAC2 by blocking its interaction with a binding partner called Sp3 to reverse memory loss in Alzheimer’s patients.’
For the study,
the research team used a larger protein fragment to interfere with HDAC2. They
plan to find small molecules that would be easier to deploy as drugs.
This is the
first time we have found a specific mechanism by which HDAC2 regulates synaptic
gene expression, said Li-Huei Tsai, senior author of the study and director of
MIT's Picower Institute for Learning and Memory.
In a study
conducted in 2007, Tsai discovered that blocking HDAC activity could reverse
memory loss in mice. There are several classes of HDACs. The primary function
of HDAC is to modify histones - protein components of chromatin, acting as
spools around the DNA. These modifications condense chromatin, making genes in
that stretch of DNA less likely to be expressed.
team found that HDAC2 is responsible for the blockade of memory-linked genes.
They also found that HDAC2 is elevated in human Alzheimer's patients and in
several mouse models of the disease.
HDAC2 serves as
a master regulator of memory gene expression. Elevated HDAC2 causes an
epigenetic blockade of the expression of those memory genes in Alzheimer's.
"If we can
remove the blockade by inhibiting the HDAC2 activity or reducing HDAC2 levels,
then we can remove the blockade and restore expression of all these genes
necessary for learning and memory," said Tsai.
available HDAC inhibitors that block HDAC2 also affect HDAC1, contributing to
toxic side effects. HDAC1 is necessary for cell proliferation, especially in
the production of white and red blood cells.
Specific Targets to Reverse Memory Loss
team conducted a study to identify proteins that help the enzyme bind to genes
required for memory formation. Initially, they analyzed gene expression data
from postmortem brain samples taken from people who did not have Alzheimer's
disease, including 28 brains with high HDAC2 levels and 35 with low levels.
They identified more than 2,000 genes whose levels closely matched HDAC2
levels, suggesting that those genes might work together with HDAC2.
Based on the
function of these genes and their interaction with HDAC2, they identified three
of genes for further testing. The tests showed that a gene called Sp3 is
necessary to recruit HDAC2 to block memory-linked genes.
gene expression data from postmortem brains of Alzheimer's patients, they found
a correlation between levels of HDAC2 and Sp3.
Study in a Mouse Model of Alzheimer's Disease
team further explored what would happen if they lowered Sp3 levels in a mouse
model of Alzheimer's disease. They found that deactivating Sp3 also restored
the mice's ability to form long-term memories.
team hopes to develop a drug in the form of a small protein or chemical
compound to potentially restore memory in Alzheimer's patients.
identified the section of the HDAC2 protein that binds to Sp3. They also
engineered neurons to overproduce HDAC2 fragment to block Sp3 from binding
HDAC2 and releasing the blockade of memory-linked genes. The fragment did not
interfere with cell proliferation, suggesting a new targeted approach that
would not have the adverse side effects of more general HDAC inhibitors.
fragment used to block the interaction has about 90 amino acids, which would be
too large to use as a drug. So research team hopes to identify a smaller
segment to disrupt the Sp3-HDAC2 interaction.
team would further investigate some of the other genes that were found to
correlate with HDAC2 to identify other drug targets. They also plan to explore
whether this approach could be useful in treating other disorders that involve
elevated levels of HDAC2, such as posttraumatic stress disorder.
The findings of
the study are published in the journal Cell Reports.
- Reversing Alzheimer's gene 'blockade' can restore memory, other cognitive functions - (http://news.mit.edu/2012/alzheimers-hdac2-inhibitors-0301)