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Therapeutic Approach Licensed By Neurogenetics, Inc. Links
Key Cellular Pathway To Alzheimer's Genes
SAN DIEGO – October 3, 2000 – Neurogenetics, Inc.
(www.neurogeneticsinc.com), a privately held biopharmaceutical
company, reported today that a study published in the September
issue of Neuron links a new mechanism-based therapeutic
approach, licensed by the Company from Massachusetts General
Hospital (MGH), to Alzheimer's disease (AD).
In the paper, Tae-Wan Kim, Ph.D., Rudy Tanzi, Ph.D., and
colleagues from the MGH Genetics and Aging Unit report that they
have discovered a key link between two cellular abnormalities
associated with the disease -- mutations in genes encoding
presenilin proteins and an altered handling of calcium inside cells.
While many cellular pathways can affect the flow of calcium into and
out of a cell, the results from MGH tie one specific pathway,
capacitative calcium entry (CCE), to the production of
amyloid-beta42 (A-beta42). A-beta42 is a sticky protein fragment
deposited in plaques found in the brains of people with AD. In
normal cells, calcium is stored in a cellular compartment called the
endoplasmic reticulum (ER), that is refilled through the CCE
process. The authors’ findings indicate that presenilin mutations
known to be associated with the inherited form of early-onset AD
inhibit the CCE process, resulting in increased production of
A-beta42. Neurogenetics has exclusively licensed from MGH the
approach of treating Alzheimer’s by modulating CCE.
Cellular regulatory processes involved in the generation of
excessive A-beta42 and reduced CCE are among the biological
mechanisms that form the foundation of Neurogenetics’ target and
drug discovery programs. “The results of our MGH colleagues have
revealed a heretofore unrecognized relationship between CCE and
presenilin- mediated increased production of A-beta42. Their
findings indicate that drugs that activate or potentiate this specific
calcium entry pathway could selectively lower levels of A-beta42, the
most pathogenic of the A-beta peptides. We expect this critical
cellular process to be affected in both early- and late-onset forms of
the disease," said Gönül Veliçelebi, Ph.D., Vice President, Biology
at Neurogenetics. Kenneth A. Stauderman, Ph.D., Project Leader
and Executive Director, Cell Biology and Physiology at
Neurogenetics, added, “Based on these findings, Neurogenetics
has developed specific, cell-based assays to identify drugs that
modulate the entry of calcium through the CCE pathway. Targeting
CCE for drug discovery represents a unique mechanistic approach
for selectively inhibiting A-beta42 production.”
Mutations in two presenilin proteins – PS1 and PS2 – have been
identified as causing most cases of inherited, early-onset AD, also
called familial Alzheimer's disease (FAD). Recent AD research has
shown that brain cells from people with FAD, or cells into which
mutated presenilin genes have been inserted, show alterations in
regulation of calcium signaling, a process that is fundamental for
normal cellular metabolism.
Many cellular activities are triggered when signaling molecules bind
to receptors on the cell surface, setting off a process called signal
transduction. A key step in signal transduction involves release of
calcium stored in the ER into the interior of the cell, which helps
translate the signal into specific cellular activities. Once the calcium
has been released, the supply in the ER must be replenished.
Movement of calcium from outside the cell into the ER utilizes CCE,
a unique pathway that differs from other modes of moving calcium
into the cell.
Previous studies had suggested that cells expressing presenilins
carrying the FAD-associated mutations showed elevated release of
calcium from the ER. The MGH team further investigated whether
these presenilin mutations had any effect on CCE. The researchers
first found that cells in which the PS1 protein was either absent or
inactivated, showed enhanced CCE, suggesting that the protein
may modulate this process. In cells with the FAD-associated
mutations in either PS1 or PS2, CCE was downregulated,
suggesting that those mutations increased the regulatory effects of
presenilins. To test whether inhibition of CCE had an impact on the
deposition of A-beta42, the researchers used cells that
overproduce the amyloid precursor protein and therefore A-beta.
They studied the effects of inhibitors of three known calcium entry
pathways and found that only the inhibition of the CCE pathway led
to increased production of A-beta42. |
