Obscure enzyme linked to both aging and Alzheimer’s disease

AUGUSTA, Ga. — A little-studied enzyme may hold the key to understanding why older adults suffer from cognitive decline and eventually develop Alzheimer’s. Researchers from Augusta University say having more of the enzyme keeps neurons healthy. Meanwhile, their study also finds these levels drop with age and decline even further in patients with dementia.

The enzyme is called HDAC9 and it’s a member of a group of enzymes which determine how tightly human DNA is wrapped. This affects gene expression. However, the new study notes that there’s also evidence that HDAC9 plays a crucial role in how neurons communicate — affecting a person’s ability to learn and remember.

Study leader Dr. Xin-Yun Lu says there are 11 HDACs (histone deacetylase) in the brain, but our DNA expresses HDAC9 most dramatically. Additionally, neurons exclusively express the enzyme, particularly in the hippocampus and prefrontal cortex — brain regions which are key to learning and memory and extremely vulnerable to Alzheimer’s.

“We need to look at why it’s decreased, and when it’s decreased, why it causes problems,” says Lu, a Georgia Research Alliance Eminent Scholar in Translational Neuroscience, in a university release.

The research team is currently studying this connection with help from a grant by the National Institute on Aging.

Aging is the major risk factor for Alzheimer’s disease, so when you look at what genes are involved in brain aging and Alzheimer’s, you look at gene expression at different ages,” Lu says.

Could HDAC9 be the first marker of Alzheimer’s development?

Lu’s team kept track of the relatively short lifespan of a mouse as levels of HDAC9 declined in the brain. On average, a lab mouse lives for roughly two years.

The team found significantly lower HDAC9 expression in the prefrontal cortex in animals with Alzheimer’s in comparison to those without the disease. They also discovered that HDAC9 expression dropped off before amyloid protein buildups appeared.

These clumps in the brain are one of the telltale signs of Alzheimer’s onset, so the new findings could point to something else happening in the brain before that takes place. Scientists removing HDAC9 from mice found that a lack of the enzyme in the body impaired the neurons’ ability to communicate — a skill scientists call synaptic plasticity.

The new study is taking a closer look at how HDAC9 levels in the hippocampus and prefrontal cortex connect to age-related cognitive decline. They’re also examining how HDAC9 expression regulates healthy synaptic plasticity in the brain.

“We need to find what neural substances mediate HDAC9’s effect on behavior and synaptic plasticity,” Lu explains.

To that end, the current study is looking at substances including the protein neuronal pentraxin2, which aids in the survival of neurons. The team says it’s important to know how HDAC9 works because, if scientists increase these levels in the brain, they can monitor how those changes affect other brain chemicals the enzyme regulates.

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