- The brain is the control center for most of the functions
throughout the body; it is also where we experience the physical
world around us and perceive our inner psychological and emotional
selves. It is where thought, love and dreams are conjured up and
where memory is embedded.
But with ever-increasing longevity we must now watch increasing
numbers of our aging friends and relatives suffer the frustrations
and humiliations as neurodegenerative diseases erode the most basic,
the most human of brain functions. Sometimes the damage is so great
that basic cognitive faculties are lost and even the uniqueness of
the individual seems to fade away. Such is the decline associated
with Alzheimer's disease. And sometimes those once strong and sturdy
are bent low with trembling gait and slurred speech as they succumb
to Parkinson's disease.

At the Hebrew University, cutting-edge research has already given
some sufferers of these diseases some of the first medical
interventions available to help control and alleviate the symptoms
of these diseases. Now ground-breaking research is pointing the way
to new understanding and novel therapies.

The brains of patients who suffer from advanced Alzheimer's disease
are wasted and shrunken. Under the microscope it becomes clear that
large numbers of neurons die and are coated with a protein-like
substance known as amyloid plaques. Within the cells a tangle of
proteins can be seen.

One approach is to investigate these tangles and plaques but
Professor Marta Weinstock-Rosin, incumbent of the Dr. Leon and Dr.
Mina Deutsch Chair in Psychopharmacology at the HU School of
Pharmacy, sees the problem differently. "If we are going to produce
a drug that can impact on and slow the progress of Alzheimer's then
we must be able to replicate its earliest stages," she says. Careful
experiments using an animal model that mimics the early symptoms of
Alzheimer's provide her with the testing ground for a new generation
of drugs to treat the disease.

Weinstock-Rosin certainly has the credentials for success. It was
her research over 20 years ago that produced RA7, now sold worldwide
under the trade name Exelon - one of the first Alzheimer's
medications. Unique among drugs used to treat Alzheimer's, Exelon
targets only specific parts of the brain and doesn't have a
deleterious effect on other parts of the body.

Marketed by the Swiss Pharmaceutical company Novartis, Exelon has
already helped hundreds of thousands of patients and has an annual
sales turnover in excess of $350 million. In June 2006 Exelon
received further FDA approval for treating mild-to-moderate dementia
associated with Parkinson's disease.

Although Exelon can do much to improve the quality of life for about
one-third of all Alzheimer's patients by slowing the progress of the
disease and improving memory skills, it only remains effective for a
few years.

Weinstock-Rosin's latest research focuses on a novel drug called
ladostigil and which combines Exelon with Rasagiline, a Parkinson's
disease treatment developed by Professor Moussa Youdim of the
Technion-Israel Institute of Technology.

Following a chance conversation between them in 1994, Weinstock and
Youdim realized that by combining their expertise and amalgamating
the active components of their respective drugs, they might produce
a more powerful new drug for combating and controlling the progress
of Alzheimer's. Their research has been funded by Israel's leading
drug company, Teva Pharmaceuticals.

Using an animal model to test the drug, some of the earliest stages
of Alzheimer's disease have been elucidated and insights have also
been provided into the workings of the normal brain.

The brain comprises two chief types of cells - neurons and glia.
Neurons are responsible for all the mental processes of
understanding; the glia provide the support and protection essential
for normal neuron function. The glia consist of different types of
cells including astrocytes which reach out with long fibrous
structures and cling to neurons, supplying them with nutrition and
oxygen. There are also microglia which act as the brain's local
immune response, devouring intruders such as viruses or bacteria
that might disturb the healthy function of the brain.

The brain, even a sleeping brain, requires a great deal of energy
which is provided through metabolism of glucose in the astrocytes.
Unfortunately, this metabolic process produces highly reactive "free
radicals" and as we get older the brain fails to produce enough of
the enzymes needed to neutralize them. Instead these oxidative free
radicals rampage through the brain, attaching themselves to cell
membranes and various proteins.

Recognizing these free radicals as dangerous intruders, the
microglia spring into action and a full-blown immune response is
initiated with special chemicals called cytokines released. The
cytokines attack the astrocytes and glucose can no longer be
metabolized. The energy supply to the brain is thus decreased, the
neurons can no longer function properly, and memory begins to fail.
Alzheimer's has claimed another victim.

Having developed a rat model that replicates these early features of
the disease, Weinstock-Rosin has been able to test the drug
ladostigil. The results are impressive: the drug is able to combat
the initial stages which lead to degeneration. It plays a key role
in restoring normal metabolic processes in the brain's support
system - the astrocytes return to their normal status, neuron
function is restored, and memory skills return.

Now nearing completion of clinical trials Phase II, ladostigil has
so far been proven a safe drug. The experiments with animal models
demonstrate that the drug can not only slow the loss of cognitive
function in Alzheimer's and Parkinson's diseases but also help
alleviate symptoms of major depression. Weinstock-Rosin is convinced
that these three debilitating forms of attack on normal brain
function have common elements.

Stressed Out

Diseases like Alzheimer's and Parkinson's do not have a single,
simple cause. In an organ as complex as the brain many processes
seem to lead to neurodegeneration.

It has become clear through the research of Professor Hermona Soreq,
Dean of the Faculty of Science and a member of the Department of
Biological Chemistry in the Alexander Silberman Institute of Life
Sciences and the University's multidisciplinary Eric Roland Center
for Neurodegenerative Diseases, that stress, both psychological and
chemical, has an impact on the progress of neurodegenerative
diseases and even affects neuromuscular and blood cell diseases.

Soreq has pioneered the development of new techniques to explore the
underlying processes which produce damage and she has successfully
identified the mechanism whereby anxiety and stress exacerbate
neurological diseases such as Alzheimer's. She is now progressing
with the development of highly innovative treatment.

Soreq is driven by a two-fold quest. "By improving our understanding
of the diseased brain, we can develop better ways to prevent and
treat," she says. "However, if we study the changes that take place
in a system pushed to the extreme, then we also learn how it
functions normally - this is a basic research goal."

In the brain a large family of neurotransmitters moves between
neurons. These chemicals form the web of communication between
neurons which is the very essence of normal brain function. The
normal brain produces a large family of neurotransmitters. They are
secreted by one brain cell, move across to another, latch on to a
receptor and thereby stimulate processes within the second cell.
Cascades of neurotransmitters create a whole web of communication
between different cells in the brain.

In Alzheimer's disease this network is disrupted. The amount of an
essential neurotransmitter, acetylcholine, drastically declines; the
connection between brain cells is broken, and memory and other brain
functions eroded.

The disappearance of this neurotransmitter under stress has been
shown by Soreq to be due to the stress-induced overproduction of
acetylcholinesterase (AChE). This enzyme actively destroys too much
acetylcholine, leaving the brain lacking a neurochemical essential
for its normal cognitive, emotional and psychological functioning.

To prevent the progress of Alzheimer's disease it is necessary to
prevent this excess elimination of acetylcholine. While existing
drugs inactivate the destructive enzyme AChE, Soreq and her team
have taken a highly original approach. They have designed a drug
which prevents AChE from even being produced by the brain.

AChE, like all enzymes, is manufactured by instructions contained in
the genetic code on a stretch of DNA in the nucleus of a cell. It
took Prof. Soreq's team five years to identify the actual gene
responsible for the manufacture of this particular enzyme. This
pioneering work involved developing completely new research tools to
carry out these technically innovative procedures.

Having identified the gene, the scientists made an inverse copy of
it. This mirror image of the gene could then lock onto the original
stretch of the gene, rather like two pieces of a jigsaw fitting
together perfectly. The new DNA-based drug clips on to the exposed
gene, making it a sealed unit and creating an unfamiliar package in
the cell. The cell immediately identifies it as an unwelcome
intruder and destroys it, just as if it were an invading virus.

This protective drug, know as Monarsen (for Prof. Soreq's
nickname "Mona") has been developed through the start-up
biopharmaceutical company, Ester Neuroscience. It is already being
administered to a group of patients as part of Phase II clinical
trials under the approval of the US Food and Drug Administration
(FDA), which has designated it as an 'orphan drug' for the treatment
of the rare muscle-wasting autoimmune disease myasthenia gravis.

Monarsen will soon be poised to enter final Phase III clinical
trials. If the drug continues to prove its efficacy, it will receive
the essential FDA approval that permits it to enter the
pharmacopoeia available to the prescribing physician. "The
development of a new drug costs well over $500 million; most of the
investment goes into this last phase," says Soreq, who is optimistic
that Ester Neuroscience will find a strategic partner for this
potentially powerful new weapon against the misery and debilitation
caused by Alzheimer's and other inflammatory diseases such as
myasthenia gravis.

Susan Goodman
May 03, 2007(Israel21C)