Targeting Enzyme May Be an Approach to Alzheimer’s Therapy

Targeting particular enzymes to cure diseases or to relieve symptoms has never been an easy task. Indiscriminate targeting often results in unnecessary potentially toxic effects. For the same reasons, early attempts to target HDAC2 were not successful.

Researchers knew that HDAC2 plays a vital role in neuroplasticity and memory formation. Now the latest research has demonstrated the more selective way of blocking HDAC2, without disrupting its other functions. Researchers achieved this by blocking sp3 molecule, which binds with HDAC2 to negatively regulate the functioning of neurons.

The latest study is published in the journal called Cell Reports; the study was the result of research led by Professor Tsai, director at the Picower Institute of learning and memory ant MIT.

Professor Tsai has been studying the role of HDAC2 in memory and neuroplasticity for more than a decade. Researchers at MIT believe that HDAC2 is the primary regulator of genes that control memory, with a raised level having an adverse effect, while a decreased level was positively associated with memory. The team at MIT also found that HDAC2 is elevated in Alzheimer’s disease.

Tsai and the team found that if HDAC2 can be inhibited, it is entirely possible that the results would be a higher expression of genes responsible for learning and memory. Therefore, it could be one of the options in improving neural functioning in Alzheimer’s.

Alzheimer’s: a growing problem

As America ages, so does the number of people living with Alzheimer’s grow. Loss of neuroplasticity, learning capabilities is to some extent characteristic of aging. As people get older so does the neurons, progressive brain-wasting due to aging and disease lead to dementia in a large number of cases.

Initially, it all starts with forgetfulness, but slowly the weakening of brain cells begins to affect all the other functions of the brain. It results in progressive cognitive decline, neuropsychiatric problems, finally, leading to disability.

Until now, there are many theories regarding the development of Alzheimer’s, but none seem to explain the disease development thoroughly. Though dementia and Alzheimer’s can develop at any age, they dominantly remain the problem of old age, with the majority of cases older than 60 years of age. At present, there are an estimated 5 million people living with Alzheimer’s in the US, and this number is expected to triple by 2050.

Synaptic plasticity and memory

It is perhaps one of the most widely accepted hypotheses regarding the functioning, or formation of our consciousness. As per this theory, our brain cells or neurons are not permanently fused to each other. Instead, these connections keep changing their strength, that is they are plastic. These changes in junctions or synapses between neurons play an essential role in learning and memory.

When we learn new things, these junctions (synapses) between the neurons change. These changes in synapses decide the way various brain cells communicate with each other, thus impacting the memory.

Prof Tsai and her team at MIT has been studying the role of the HDAC2 enzyme in learning and memory. More than a decade ago they discovered that blocking HDAC could reverse the memory loss in a mouse. But HDAC is not a single type of enzyme; it is rather a group of enzymes that are very similar in structure to each other. At present, more than a dozen of HDAC enzymes have been identified.

HDAC2 negatively associated with memory and brain plasticity

Histone deacetylase 2 (HDAC2) works by altering histones in genes. Histones help to bundle the genes into a package called chromatin. HDAC2 works to better zip or compact chromatin, which has an adverse effect on the expression of some of the genes including those that play a role in the learning and memory.

The team at MIT found out that in Alzheimer’s, HDAC2 is elevated, which resulted in the blockage of genes responsible for the better functioning of memory and brain cells in general. They also found the HDAC was raised not only in humans but mouse models of Alzheimer’s disease.

The next logical step in the study was to identify the compounds that safely inhibit the activity of HDAC2. Although such compounds were found, they had toxic effects, as they were not selective to HDAC2. One of the compounds, which they tested also interfered with the activity of HDAC1, which is necessary for the growth of red and white blood cells.

The team at MIT also continued to study the genes that were related to learning and were associated with the activity of HDAC2 in the brain. For this purpose, they compared the data from hundreds of samples received through a post-mortem. They analyzed the samples with elevated and those with a low level of HDAC2. The team identified more than 2000 genes that play a role in memory, and are related to the activity of HDAC2.

Sp3 facilitated recruitment of HDAC2 to synaptic genes, helping it to block memory genes

The team at MIT knew the importance of inhibiting HDAC2 and started to look at options that would suppress it in a more selective way. In their search, they found three candidates.

One such candidate identified was sp3. It is a so-called transcription factor and is required by HDAC2 to alter the chromatin, effectively blocking the genes related to learning and memory. Their analysis from the brain samples of those who died from Alzheimer’s demonstrated the higher level of both the HDCA2 and sp3.

Researchers started to focus on reducing the concentration of sp3 in the brain. In mouse models, they demonstrated that reduction in sp3 also resulted in the reduced activity of HDAC2 on memory-related genes on DNA, effectively improving the learning.

The team at MIT was able to find the chemical compound that could reduce the activity of sp3, and prevent it from binding with HDAC2. In animal models, they demonstrated that such an approach was selective to HDAC2 in brain cells, and does not interfere with other functions controlled by HDCA like the proliferation of blood cells.

Professor Tsai says that this really raises the hope, as now the need is to find a molecule that is small and could safely inhibit the sp3 in living beings. This research also opens the doors to further research on the subject of HDCA2 and silencing or activation of other genes that are regulated by it.

In conclusion, MIT found that sp3 and HDAC2 complex worked together to silence the genes responsible for learning and memory. They found that inhibiting the sp3 would decrease the activity of HDAC2 selectively. Hence, targeting the HDAC2-sp3 could be the way for finding a feasible therapy for Alzheimer’s.

References

1. Guan J-S, Haggarty SJ, Giacometti E, et al. HDAC2 negatively regulates memory formation and synaptic plasticity. Nature. 2009;459(7243):55-60. doi:10.1038/nature07925.
2. Takeuchi T, Duszkiewicz AJ, Morris RGM. The synaptic plasticity and memory hypothesis: encoding, storage and persistence. Philos Trans R Soc Lond B Biol Sci. 2014;369(1633). doi:10.1098/rstb.2013.0288.
3. Yamakawa H, Cheng J, Penney J, et al. The Transcription Factor Sp3 Cooperates with HDAC2 to Regulate Synaptic Function and Plasticity in Neurons. Cell Reports. 2017;20(6):1319-1334. doi:10.1016/j.celrep.2017.07.044.