Every year, far too many people will see their parents and grandparents reduced to a shadow of who they once were — frightened, confused, and forgetful. Alzheimer’s disease (AD) currently affects 5.7 million Americans, making it the sixth leading cause of death in the United States, and the fifth leading cause of death worldwide. Another 16.1 million will provide unpaid care for a loved one with the disease — one where often the best treatment is what will keep them content — hoping to allay their worst moments and fears as they struggle with austere and unfamiliar surroundings.
Fortunately, the findings of a new study published this year could subdue the disorder’s worst symptoms — reversing memory loss. Researchers studying epigenetics at the University of Buffalo found ways to reverse the decline of memory in mice.
“We have not only identified the epigenetic factors that contribute to the memory loss, we also found ways to temporarily reverse them in an animal model of AD,” said the study’s senior author, Zhen Yan, a SUNY Distinguished Professor in the department of physiology and biophysics at the Jacobs School of Medicine and Biomedical Sciences.
The inability to form new memories while holding onto old ones, occurs largely in the later stages of AD — when the disease can no longer be mistaken for simple forgetfulness. Yan’s team found that this was due to the disappearance of glutamate receptors, a crucial neurotransmitter of the central nervous system, involved in learning and regulation.
“We found that in Alzheimer’s disease, many subunits of glutamate receptors in the frontal cortex are down-regulated, disrupting the excitatory signals, which impairs working memory,” Yan said.
These receptors, which also play a role in synaptic plasticity — the ability of neurons to strengthen and form new connections over time, fall apart due to a process known as repressive histone modification, which escalates in patients with AD. The protein making up the receptors alters in its shape — making it difficult for the receptors to connect and interact with other cells in the body. We make a new memory every time we try to recall an old one — a reason why they can often change over time. Think of it as trying to play an old CD — the more scratched the surface, the more difficult it is to hear the music again.
Once Yan and her fellow researchers understood the mechanism, they came up with a plan to counteract it: an enzyme inhibitor, which they injected into the mice three times. What followed was a dramatic improvement — as they moved about their cages with significantly better spatial memory and recognition that they showed before their dementia symptoms.
“We saw the recovery of glutamate receptor expression and function in the frontal cortex,” Yan recalls. The mice showed cognitive improvement for a week — future study will look at compounds that can more effectively penetrate the frontal cortex and have a longer lasting effect. Human AD patients in the future could live out happier, more productive lives when such a solution is found — sustaining themselves independently without the fear or depression that often accompany waning memories. More significantly, the UB researchers have taken an epigenetic approach in their research, one that not only controls a single gene, but many — as disorders like AD are often the result of multiple gene expressions gone awry.
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