Late-life depression is a major risk factor for Alzheimer's disease, in particular because it accelerates progression from mild cognitive impairment to dementia. How this happens remains largely unknown but likely involves synapses – the junctions between neurons where information is exchanged. Synapses are essential to the ability to remember and to experience emotion.
Now, Victor M. Luna, PhD, Assistant Professor in the Department of Neural Sciences and the Alzheimer's Center at Temple at the Lewis Katz School of Medicine at Temple University, has a chance to explore synapse function in the aging brain, thanks to a new Alzheimer's Association Research Fellowship to Promote Diversity (AARF-D) award. The AARF-D is intended to support exceptional scientists from underrepresented groups who are working in areas of dementia research.
Dr. Luna's AARF-D-funded research is revolutionary in the study of Alzheimer's disease for its innovative use of pharmacology, RNA interference, and optogenetics, in which light and genetic technologies are combined to control cellular events in real time while mice are performing behavioral tasks. The research will make use of a novel mouse model, whereby mice express both Alzheimer-like characteristics and a light-sensitive version of a synaptic protein known as mGluR2, which is involved in memory formation. As the mice age, the researchers will explore synapse function and the ability of two novel drug interventions to dispel cognitive impairments related to aging.
The findings of Dr. Luna's new work promise to shed light on whether synapses can be repaired to treat symptoms related to conditions of aging, such as late-life depression and Alzheimer's disease.
Understanding how aged synapses control memory and emotion is key to developing treatments for conditions that involve aging-related cognitive decline. However, what we currently know about synapses is based mostly on studies in young animals, and now there is substantial need to better understand how synapses operate in the aged brain."
Dr. Victor M. Luna, PhD, Assistant Professor in the Department of Neural Sciences and the Alzheimer's Center at Temple at the Lewis Katz School of Medicine at Temple University
Dr. Luna and colleagues will investigate synapse function in a part of the brain known as the dentate gyrus, which is located in the hippocampus. The dentate gyrus is a center for emotion and cognition and is involved in behavioral pattern separation, in which the brain effectively distinguishes between two highly similar emotional contexts. Behavioral pattern separation, impairments of which manifest in Alzheimer's disease as overgeneralization and confusion, is facilitated by the unique ability of the dentate gyrus to make new neurons, even in adulthood.
In preliminary research, Dr. Luna and colleagues found that during aging, the loss of new neuron production, known as adult hippocampal neurogenesis (AHN), is related to changes in mGluR2. The mGluR2 protein is activated by glutamate, the most abundant signaling molecule in the brain and serves a central role in learning and memory. Reductions in mGluR2 that take place during aging allow glutamate signaling to go unchecked in the dentate gyrus, resulting in extraneous signals that undermine behavioral pattern separation.
Pilot experiments carried out by Dr. Luna's team showed that by increasing mGluR2 levels in aged mice, the animals regained their ability to perform behavioral pattern separation. Using existing drugs available to target mGluR2, which were originally developed for non-Alzheimer's purposes, he hopes to establish proof-of-concept to advance the work to preclinical trials.
"By the end of our grant period, we expect to have evaluated the effectiveness of two new therapeutic targets for rescuing behaviors related to late-life depression and Alzheimer's disease," he said. "Ultimately, we envision pharmacological synapse repair to be a safe and potent treatment for relieving late-life depression and other psychiatric symptoms of Alzheimer's disease."
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