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One of the characteristic features of Alzheimer's
disease is the deposition of amyloid ß-peptides in the brain. These
amyloid ß-peptides are derived from a large amyloid precursor protein
through a series of cleavage events. Under normal conditions, cleavage
first by a-secretase and then by ?-secretase results in a soluble
ectodomain, a short peptide called p3, and an intracellular C-terminal
domain, none of which are amyloidogenic. Alternatively, amyloid
precursor protein can be processed by the enzymes ß-secretase and ?-secretase
to produce a soluble ectodomain along with the full-length
amyloidogenic amyloid ß-peptide and the intracellular C-terminal
domain.
Although amyloid precursor protein is found in many
cells, its normal biological function is not well understood. "It has
been suggested that amyloid precursor protein may function as a
receptor or growth factor precursor," notes Dr. Xuemin Xu of The
University of Tennessee. "Recent studies also suggest that the
intracellular C-terminal domain of the amyloid precursor protein may
function as a transcription factor."
While the exact pathogenic role of amyloid
ß-peptide in Alzheimer's disease has not yet been definitely
established, accumulating evidence supports the hypothesis that
amyloid ß-peptide production and deposition in the brain could be a
causative event in Alzheimer's disease. Dr. Xu explains that the
literature indicates amyloid ß-peptide itself could be toxic to
synapses and the accumulation of amyloid ß-peptide could initiate a
series of events contributing to cell death, including activation of
cell death programs, oxidation of lipids and disruption of cell
membranes, an inflammatory response, and possibly neurofibrillary
tangle formation, which is a close correlate of neuron loss. Therefore,
the problem of production, accumulation, and clearance of amyloid
ß-peptide in the brain emerges as one of the possible rational
approaches for the treatment of Alzheimer's disease.
Generally, amyloid ß-peptides are around 39-43
amino acid long. Studies have shown that the longer amyloid ß-peptides
are more amyloidogenic and more pathogenic than the shorter ones. Now,
Dr. Xu and his colleagues have discovered a new species of amyloid
ß-peptide that is 46 amino acids long, called Aß46. This Aß46
peptide is produced by ?-secretase at a novel cleavage site, the
?-site. This site also happens to be the site of a mutation found in
early-onset familial Alzheimer's disease called the APP717 or London
mutation.
"Another well characterized Alzheimer's
disease-linked amyloid precursor protein mutation, the Swedish
mutation, also occurs at a major cleavage site, the ß-cleavage site at
the N-terminus of amyloid ß-peptide," adds Dr. Xu. "Studies have shown
that Swedish mutation at the ß-cleavage site makes the amyloid
precursor protein more susceptible to ß-secretase activity. The
finding that ?-cleavage site is the APP717 mutation site suggests that
the APP717 mutation may cause enhanced production of the longer
amyloid ß-peptide, Aß42, by influencing the ?-cleavage.
Therefore, this finding may open a new avenue for studying the
mechanism by which APP717 mutations cause enhanced production of the
longer amyloid ß-peptide."
Dr. Xu and his colleagues also discovered that ?-secretase
cleavage at the new ?-site is specifically inhibited by compounds
known as transition state analogs, but is less affected by compounds
known as non-transition state inhibitors. Specifically, some of these
inhibitors, which were previously known to inhibit the formation of
secreted amyloid ß-peptides, were found to cause an intracellular
accumulation of an even longer amyloid ß-peptide species, Aß46.
"These novel findings provide information important for the strategy
of prevention and treatment of Alzheimer's disease, aimed at the
design of ?-secretase inhibitors," concludes Dr. Xu. "Since amyloid
ß-peptide is produced by the sequential actions of ß- and ?-secretases,
inhibition of these secretases to reduce the production of amyloid
ß-peptide is believed to be one of the more promising avenues of
treatment of the disease. To date, more than one dozen ?-secretase
inhibitors have been developed or identified." |
