Good News on the Alzheimer's Front

The number of Alzheimer’s victims worldwide is expected to double every 20 years... MIT neuroscientists have shown that an enzyme overproduced in the brains of Alzheimer’s patients creates a blockade that shuts off genes necessary to form new memories. Furthermore, by inhibiting that enzyme in mice, the researchers were able to reverse Alzheimer’s symptoms.

The finding suggests that drugs targeting the enzyme, known as HDAC2, could be a promising new approach to treating the disease, which affects 5.4 million Americans.

Histone deacetylases (HDACs) are a family of 11 enzymes that control gene regulation by modifying histones — proteins around which DNA is spooled, forming a structure called chromatin. When HDACs alter a histone through a process called deacetylation, chromatin becomes more tightly packaged, making genes in that region less likely to be expressed.

HDAC inhibitors can reverse this effect, opening up the DNA and allowing it to be transcribed.

In previous studies, Tsai had shown that HDAC2 is a key regulator of learning and memory. In the new study, her team discovered that inhibiting HDAC2 can reverse Alzheimer’s symptoms in mice._MIT

As the populations of the developed and emerging nations grow progressively older, the number of Alzheimer's sufferers -- and sufferers of other debilitating diseases of old age -- threaten to cripple these societies. Affordable means of preventing and treating dementias and other disabling diseases of senescence could make the difference between prosperity or poverty for many nations. The recent MIT discovery may be an important step forward in this regard.

... the team subsequently showed that using RNAi to reduce HDAC2 build up in the hippocampus of a mouse neurodegenerative disease model removed this repression, reinstated neuronal structural and synaptic plasticity, and eradicated neurodegeneration-associated memory deficits. Li-Huei Tsai, Ph.D., and colleagues report their findings in Nature in a paper titled “an epigenetic blockade of cognitive functions in the neurodegenerating brain.”

Epigenetic modifications in the nervous system that are mediated by histone acetylation have been unequivocally associated with facilitating learning and memory, the researchers state. Multiple studies have in addition reported that reduced histone acetylation is associated with cognitive decline in animal models of neurodegeneration including AD.

To further investigate the role of HDAC2 in neurodegeneration-related cognition, the team looked at levels of the enzyme in CK-p25 mice. These animals can be induced to overexpress p25, in the forebrain. p25 is a truncated version of p35 and is implicated in a range of neurodegenerative diseases. Their studies showed that animals induced to overexpress p25 demosntrated significant increases in HDAC2 in neuronal nuclei, specifically hippocampal area CA1 but not CA3 or the dentate gyrus, and also in the prefrontal cortex. In contrast, levels of the HDAC1 and HDAC3, were not changed.

The researchers then moved on to carry out chromatin immunopreciptation studies to assess the functional consequences of HDAC2 elevation, primarily in a range of known HDAC2 targets that have been shown to be downregulated in human AD brains, including learning- and memory-related genes, and those involved in synaptic plasticity. They found elevated HDAC2 enrichment at the majority of these genes induced CK-p25 hippocampus, whereas again, HDAC1 and HDAC3 binding wasn’t affected. “Interestingly, in agreement with previous reports showing that HDAC2 can also bind to a gene’s coding region, we also found HDAC2 more abundantly bound to the coding sequence of the same genes,” they note. _GenengNews

The researchers found that in mice with Alzheimer’s symptoms, HDAC2 (but not other HDACs) is overly abundant in the hippocampus, where new memories are formed. HDAC2 was most commonly found clinging to genes involved in synaptic plasticity — the brain’s ability to strengthen and weaken connections between neurons in response to new information, which is critical to forming memories. In the affected mice, those genes also had much lower levels of acetylation and expression.

“It’s not just one or two genes, it’s a group of genes that work in concert to control different phases of memory formation,” Tsai says. “With such a blockade, the brain really loses the ability to quickly respond to stimulation. You can imagine that this creates a huge problem in terms of learning and memory functions, and perhaps other cognitive functions.”

The researchers then shut off HDAC2 in the hippocampi of mice with Alzheimer’s symptoms, using a molecule called short hairpin RNA, which can be designed to bind to messenger RNA — the molecule that carries genetic instructions from DNA to the rest of the cell.

With HDAC2 activity reduced, histone acetylation resumed, allowing genes required for synaptic plasticity and other learning and memory processes to be expressed. In treated mice, synaptic density was greatly increased and the mice regained normal cognitive function. _MIT

The MIT researchers have utilised a number of different advances in cell and molecular biology to make these discoveries. As scientists close in on the discovery of meaningful interventions in destructive pathological processes, the importance of pre-existing replicated "off the shelf" research grows.

This is good news for all mice who suffer from Alzheimer's. Now, scientists must confront the immense government-made mine field and obstacle course which obstructs modern efforts to affordably develop life saving interventions in the biomedical fields, for humans. In this sense -- as in many others -- government is the greatest enemy of the future.

Cross-posted from Al Fin