Age-Associated Memory Loss Might Be Reversable

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PNAS EMBARGO: 5 p.m. EDT Monday, September 13

AGE-ASSOCIATED MEMORY LOSS MIGHT BE REVERSIBLE

Researchers from the University of California, San Diego and the Salk Institute for Biological Studies have identified a process by which the normal primate brain degenerates with aging, and have also shown that this degeneration can be reversed by gene therapy.

While normal aging often results in some loss of memory and other cognitive functions, scientists have been unable to pinpoint changes in specific anatomical regions of the brain associated with these processes which might explain this decline.

New research published in the September 14 issue of the Proceedings of the National Academy of Science (PNAS) suggests that the age-related breakdown is occurring in the cells of the system that activates brain function in the hippocampus and cortex, which are the primary sites of memory, selective attention and other cognitive functions.

The good news is that in primates, the degeneration that occurs in this system appears to be almost completely reversible when tissue grafts of genetically modified cells that deliver human nerve growth factor (NGF) to the impaired cells are implanted in the brain.

The PNAS study was conducted in rhesus monkeys, which provide a good model for human aging. The target of the study was the subcortical system, a signaling system of cholinergic neurons that regulate cortical and hippocampal activity. The monkeys were housed at the California Regional Primate Research Center at the University of California, Davis.

"Our findings show that with normal aging, there is a significant loss of function and shrinkage in size of neurons in a subcortical system called the 'cholinergic system'," said the senior author of the PNAS paper Mark Tuszynski, M.D., Ph.D., associate professor of neurosciences at the University of California, San Diego School of Medicine and neurologist with the Veterans Affairs San Diego Health Care System. "These cholinergic neurons, through the release of neurotransmitters, basically regulate the voltage and activity of cells in the cortex and hippocampus, allowing the cortex to process information and function normally. They essentially 'prime' the brain to function, so, if as a result of normal aging their activity is turned down, the brain's ability to process information is hampered.

"Equally important is the evidence that these neurons are not dead, just atrophied with aging. They can be returned to what appears to be a normal state with a gene therapy approach that delivers NGF to the cells," he said.

According to Tuszynski, these findings have implications not only for cognitive function in normal aging, but might also be significant in preventing some of the cognitive decline in neurodegenerative conditions such as Alzheimer's disease, in which this same system of cells is known to undergo profound atrophy and death.

Four groups of monkeys were studied. One group of young monkeys and a group of normal aged monkeys were compared in order to identify the changes in neurons associated with age. In addition, a group of aged monkeys which received brain grafts of genetically modified NGF-secreting tissue, and a control group of aged monkeys which received non-NGF grafts, were studied to see whether NGF tissue grafts would have any effect. NGF is essential for the normal development of these neurons in the fetus, and the brain remains sensitive to NGF throughout life.

In the normal aged monkeys, the number of subcortical cholinergic neurons making proper amounts of neurotransmitters and receptors for growth factors declined by 43 percent compared with the young monkeys, and the remaining neurons were 10 percent smaller. The aged control monkeys with non-NGF-secreting tissue implants showed identical losses.

However, aged monkeys which received NGF-secreting grafts showed an almost complete restoration of normal cell function in 92 percent of neurons, and size returned to within 3 percent of normal.

"Normal aging affects not only memory, but perhaps more importantly things like attention, the ability to focus on multiple tasks at once, and the overall efficiency of thought processes," said Tuszynski. "In the case of conditions like Alzheimer's disease, which affects approximately 4 million people, this decline in function is even more severe. These findings give us a new avenue to pursue in trying to enhance these functions in both the normal aged brain and in the diseased brain."

This study looked strictly at the measurable physical indications of atrophy and regeneration. Tuszynski said studies also are being done to evaluate behavioral and functional changes.

Co-authors of the PNAS paper are David Smith, M.S., a graduate student at the UCSD School of Medicine; Jeff Roberts, D.V.M., of the California Regional Primate Research Center at UC Davis; and Fred H. Gage, Ph.D., of the Salk Institute for Biological Studies.

This work was supported by grants from the National Institutes of Health, the Department of Veterans Affairs, and the California Regional Primate Research Center.

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