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A new protein discovered by TAU and NIH scientists promises blocking action
against the neurological symptoms of AIDS dementia and Alzheimer's disease
Floating in a sea of fluid, surrounded by two sturdy membranes and encased in
a skull of solid bone, the human brain is well protected from the buffets of
the outside world. This armor is crucial because during the entire human life
span, the brain's delicate nerve cells (neurons), once damaged or dead, do
not replace themselves - causing irreversible loss. This protection
not-withstanding, brain cells are still highly susceptible to chemical damage
from within by neurotoxins, oxygen radicals, oxygen, and glucose deprivation.
The brain's natural defense against neuronal cell damage is in the form of
small proteins known as neurotrophic factors (NTF). Scientists have already
identified several NTFs, but the discovery of a new NTF - named ADNF - by TAU
neurochemist Prof. Illana Gozes together with Dr. Douglas E. Brenneman of the
US National Institutes of Health (NIH), recently made headlines for its
potential therapeutic benefits in treating brain cell damage associated with
the AIDS virus and Alzheimer's disease.
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ADNF protects cultured nerve cells from death by the
electrical
activity-blocking toxin tetrodotoxin at exeptionally low levels, while other
nerve growth factors do not." |
Prof. Gozes, who was recently elected incumbent of the Lily and Avraham Gildor
Chair of Neurotrophic Factor Research, notes that the new protein has distinct
advantages over other known NTFs: it is highly effective at 1000-to a million
times lower concentrations. In addition, one segment of the ADNF molecule -
only 14 amino acids long (ADNF/14) - was found to provide neurons the same
broad-spectrum defense as the entire ADNF molecule, making it more promising
for drug therapy since smaller proteins can more easily penetrate into the
brain.
When neurons are electrically active, they produce and excrete vasoactive
intestinal peptide (VIP) which, in turn, induces nearby astroglial cells
(the "glue" cells between neurons) to produce NTFs, including ADNF. When
neuronal activity is blocked by toxins such as tetrodotoxin, however, VIP and
ADNF are not produced in sufficient quantities, and some neurons aptly named
"activity-dependent" (ADN) die. In the course of experiments, the researchers
found that minute doses of VIP cause the astroglial cells to secrete ADNF
thereby preventing ADN cell death. For example, even at extremely low
concentrations, ADNF protein protected the neurons of the spinal cord against
tetrodotoxin damage and death. In contrast, other NTFs had little effect.
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Neurons (left)
stimulate nearby astroglial ("glue") cells (right) to produce ADNF. |
The investigators also found that part of the ADNF structure includes a
segment similar to a protein which protects neuronal cell structure when the
body is exposed to stressful conditions (a stress protein). However, unlike
stress proteins which are produced and act inside the cell, ADNF is excreted
into the intercellular fluid and serves as an intermediary between cells -
perhaps as a protector of the normal spatial structure of the surrounding
components between brain cells.
To probe the exact nature of ADNF protection, Prof. Gozes and Dr. Brenneman,
together with former TAU doctoral student Dr. Ariane Davidson, produced
anti-ADNF antibodies in animals. These antibodies caused destruction of nerve
cells, proving that ADNF has an important role as a natural protector against
neuronal destruction.
Findings of the research were recently reported in The Journal of Clinical
Investigation and the researchers' proposal to use an inhalable formulation
to help treat Alzheimer's was published in the Proceedings of the National
Academy of Sciences (US).
The research at TAU was carried out at the Krinkin-Stern Wing for Research in
Chemical Pathology, the Sackler Faculty of Medicine.
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