Apr 04, 2002 AXONYX INC. (NASDAQ - AXYX) - Results reported in an abstract on the transgenic mouse confirmed that Phenserine, a third generation acetylcholinesterase inhibitor (AChE-inhibitor), has the ability to reduce both amyloid precursor protein (APP) and amyloid peptide (amyloid-beta) formation in the brain which could have important potential implications for the treatment of Alzheimer's Disease (AD).
Dr. Nigel Greig of the National Institute on Aging/National Institutes of Health
(NIA/NIH), together with collaborators that included Dr. Debomoy Lahiri (Indiana
University School of Medicine) and Dr. Kumar Sambamurti, presented data in a
poster session today, entitled "Amyloid-Modifying Properties of The
Acetylcholinesterase Inhibitor, Phenserine," at The 7th International
Geneva/Springfield Symposium on Advances in Alzheimer Therapy, April 3 - 6, 2002
in Geneva.
"Unlike other acetylcholinesterase inhibitors that simply suppress the activity
of the enzyme, Phenserine's dual mechanism of action, to reduce amyloid-beta
levels via its actions on APP, suggests that it not only has the potential to
improve memory and cognition, but also to slow the progression of the disease,"
reported Drs. Greig, Lahiri, Sambamurti and colleagues.
The neurotoxic peptide, amyloid-beta, that is the core constituent of the
plaques found in the AD brain, is generated by the proteolytic cleavage of APP
by a group of enzymes whose inhibition is a strategy for AD treatment.
Significantly however, and unassociated with its acetylcholinesterase action,
phenserine reduces the synthesis of APP to a level that retains its
physiological function but that reduces the amyloid-beta derived from it.
Lowering amyloid-beta levels is achieved without affecting APP proteolytic
enzymes, which are reported to possess other critical functions. Reducing
amyloid-beta formation and its resulting deposition could favorably modify AD
progression.
Study Results
The objective of the research was to determine the effect of Phenserine on the
levels of APP and amyloid-beta in tissue culture and assess whether or not
tissue culture results translated to an in vivo transgenic mouse model. Double
transgenic mice that over-express human APP and amyloid-beta were treated with
either saline or phenserine for three weeks. Thereafter, brain and
cerebral-spinal fluid (CSF) levels of APP and brain levels of amyloid-beta were
quantified and compared.
The results of the study indicate that Phenserine:
-- Reduced APP and amyloid-beta levels in neural cells in tissue
culture: This occurred by reducing APP synthesis rate via a
post-transcriptional mechanism.
-- Reduced APP in transgenic mice: Compared to controls,
Phenserine reduced APP levels by 10% (p less than 0.05) in
cerebral cortex and 55% (p less than 0.05) in CSF.
-- Reduced amyloid-beta in transgenic mice: Levels of
amyloid-beta were reduced by in excess of 50%.
This study confirms and extends research announced last year by Drs. Greig,
Lahiri, Sambamurti and colleagues in the "Proceedings of the National Academy of
Sciences (2001 Jun19:98(13):7605-10)" highlighting Phenserine's ability to
inhibit the formation of APP and amyloid-beta in tissue culture and defining the
mechanism involved.
"Scientists are now acknowledging that Alzheimer's Disease involves a complexity
of connected cascade-like events," stated Marvin S. Hausman, M.D., President and
CEO, Axonyx Inc. "Phenserine's novel dual mechanism of action has the potential
to usher in a different therapeutic approach to controlling this tragic
disease."
