John johnhkm at
Wed Sep 15 22:38:38 EST 1999


September 8, 1999

Media contact:  Leslie Franz, UCSD,  (619) 543-6163

For Salk: Suzanne Clancy (858) 453-4100 ext. 1340
               Warren Froelich  (858) 453-4100 ext. 1646


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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