Recognizing late-life depression as a significant precursor to Alzheimer's disease, primarily due to its ability to fast-track the transition from mild cognitive dysfunction to full-blown dementia, researchers are delving deep into the mechanisms that underpin this progression. The focal point of their interest is synapses, the critical neural junctions that facilitate the exchange of information, pivotal for memory and emotional experience. At the forefront of this exploration is Victor M. Luna, PhD, Assistant Professor at the Department of Neural Sciences and the Alzheimer’s Center at the Lewis Katz School of Medicine, who has received the Alzheimer’s Association Research Grant to Promote Diversity - New to the Filed (AARG-D-NTF). This award aims to boost the work of outstanding scientists from underrepresented groups in dementia research.
Through the AARG-D-NTF grant, Dr. Luna's investigation stands out in Alzheimer’s research for its pioneering application of pharmacology, RNA interference, and optogenetics—a blend of light and genetic technologies—to manipulate cells in living mice as they undertake behavioral actions. His project leverages an innovative mouse model that manifests features of Alzheimer's alongside a light-activated synaptic protein, mGluR2, crucial for memory formation. With aging mice as subjects, the study will probe synaptic functions and assess the efficacy of two groundbreaking drug treatments in mitigating cognitive deficits associated with aging.
Dr. Luna's research is set to illuminate possibilities for synaptic repair as a strategy to alleviate conditions akin to late-life depression and Alzheimer’s disease. "Grasping the dynamics of aged synapses in memory and emotional regulation is critical for developing interventions for aging-related cognitive decline," Dr. Luna states. He emphasizes the gap in understanding how synapses function in aged brains, contrasting with insights drawn from young animal studies, highlighting the urgent need for this new research.
The study will focus particularly on the dentate gyrus area of the hippocampus, a brain region integral to cognition and emotion, and known for its role in behavioral pattern separation—a cognitive process where the brain distinguishes between similar emotional contexts. This ability is crucial in preventing overgeneralization and confusion seen in Alzheimer’s disease, facilitated by the dentate gyrus's unique capacity to generate new neurons throughout adulthood.
Initial findings by Dr. Luna and his team reveal that aging correlates with a decline in production of new neurons, or adult hippocampal neurogenesis (AHN), which links to alterations in mGluR2. This protein, activated by glutamate—the predominant neurotransmitter in the brain vital for learning and memory—experiences a reduction with age. This decline disrupts glutamate signaling in the dentate gyrus, leading to erratic signals that impair behavioral pattern separation.
Preliminary studies by Dr. Luna’s group have demonstrated that enhancing mGluR2 levels in older mice restores their ability to differentiate between behavioral patterns. By utilizing drugs that target mGluR2, initially intended for non-Alzheimer's applications, Dr. Luna aims to provide a proof-of-concept that could pave the way for preclinical trials.
“By the conclusion of our grant term, we anticipate validating the potential of two novel therapeutic targets for addressing symptoms associated with late-life depression and Alzheimer's disease,” Dr. Luna elaborated. “Our goal is to establish pharmacological synapse repair as a viable and effective treatment for mitigating the psychiatric manifestations of Alzheimer's disease, including late-life depression.”