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The Journal of Neuroscience, March 1, 1998, 18(5):1743-1752
Turnover of Amyloid  -Protein in Mouse Brain and Acute
Reduction of Its Level by Phorbol Ester
Mary J.
Savage,
Stephen P.
Trusko,
David S.
Howland,
Leonard R.
Pinsker,
Suzanne
Mistretta,
Andrew G.
Reaume,
Barry D.
Greenberg,
Robert
Siman, and
Richard W.
Scott
Cephalon, Inc., West Chester, Pennsylvania, 19380
Fibrillar amyloid deposits are defining pathological lesions in
Alzheimer's disease brain and are thought to mediate neuronal death.
Amyloid is composed primarily of a 39-42 amino acid protein fragment
of the amyloid precursor protein (APP), called amyloid  -protein
(A). Because deposition of fibrillar amyloid in vitro has been shown to be highly dependent on A concentration, reducing the proteolytic release of A is an attractive, potentially
therapeutic target. Here, the turnover rate of brain A has been
determined to define treatment intervals over which a change in
steady-state concentration of A could be measured. Mice producing
elevated levels of human A were used to determine approximate
turnover rates for A and two of its precursors, C99 and APP. The
t1/2 for brain A was between 1.0 and 2.5 hr, whereas for C99, immature, and fully glycosylated forms of
APP695 the approximate t1/2 values
were 3, 3, and 7 hr, respectively. Given the rapid A turnover rate,
acute studies were designed using phorbol 12-myristate 13-acetate (PMA), which had been demonstrated previously to reduce A secretion from cells in vitro via induction of protein kinase C
(PKC) activity. Six hours after intracortical injection of PMA, A
levels were significantly reduced, as measured by both A40- and
A42-selective ELISAs, returning to normal by 12 hr. An inactive
structural analog of PMA, 4 -PMA, had no effect on brain A levels.
Among the secreted N-terminal APP fragments, APP levels were
significantly reduced by PMA treatment, whereas APP levels were
unchanged, in contrast to most cell culture studies. These results
indicate that A is rapidly turned over under normal conditions and
support the therapeutic potential of elevating PKC activity for
reduction of brain A.
Key words:
protein turnover; amyloid- protein; amyloid
precursor protein; Alzheimer's disease; phorbol ester; protein
kinase C
Copyright © 1998 Society for Neuroscience 0270-6474/98/1851743-10$05.00/0
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