A scientific team from the Scripps Research Institute (TSRI), the Veterans Affairs San Diego Healthcare System (VA), and University of California (UC) San Diego School of Medicine reports that increasing a crucial cholesterol-binding membrane protein in neurons within the brain can improve learning and memory in aged mice.

“This is a novel strategy for treating neurodegenerative diseases, and it underscores the importance of brain cholesterol,” said Chitra Mandyam, Ph.D., associate professor at TSRI and co-first author of the study (“Neuron-targeted caveolin-1 improves molecular signaling, plasticity and behavior dependent on the hippocampus in adult and aged mice”) that appears online in Biological Psychiatry.

Senior author Brian Head, Ph.D., a research scientist with the VA and associate professor at UC San Diego, added, “By bringing back this protein, you're actually bringing cholesterol back to the cell membrane, which is very important for forming new synaptic contacts.”

The research focuses on a specific membrane protein called caveolin-1 (Cav-1) and expands scientists' understanding of neuroplasticity, the ability of neural pathways to grow in response to new stimuli.

Previous work by Dr. Head's group at the VA and at UC San Diego had shown that raising Cav-1 levels supported healthy “rafts” of cholesterol involved in neuron growth and cell signaling. However, it wasn't clear if this new growth actually improved brain function or memory.

To find out, the researchers delivered Cav-1 directly into the hippocampus in adult and “aged” mice. The hippocampus is a structure thought to participate in formation of contextual memories, e.g., if one remembers a past picnic when later visiting a park.

In addition to improved neuron growth, treated mice demonstrated better retrieval of contextual memories, i.e., they froze in place, an indication of fear, when placed in a location where they'd once received small electric shocks.

Drs. Mandyam and Head believe that this type of gene therapy may be a path toward treating age-related memory loss. The researchers are now testing this gene therapy in mouse models of Alzheimer's disease and expanding it to possibly treat injuries such as spinal cord injury and traumatic brain injury.

This new understanding of Cav-1 and neuroplasticity could also be relevant to memory loss due to alcohol and drug use, according to Dr. Mandyam.

“We're very interested in studying whether we can manipulate Cav-1 in other areas of the brain,” said Dr. Mandyam.

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