RT Journal Article
SR Electronic
T1 Turnover of Amyloid β-Protein in Mouse Brain and Acute Reduction of Its Level by Phorbol Ester
JF The Journal of Neuroscience
JO J. Neurosci.
FD Society for Neuroscience
SP 1743
OP 1752
DO 10.1523/JNEUROSCI.18-05-01743.1998
VO 18
IS 5
A1 Mary J. Savage
A1 Stephen P. Trusko
A1 David S. Howland
A1 Leonard R. Pinsker
A1 Suzanne Mistretta
A1 Andrew G. Reaume
A1 Barry D. Greenberg
A1 Robert Siman
A1 Richard W. Scott
YR 1998
UL http://www.jneurosci.org/content/18/5/1743.abstract
AB 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 β-protein (Aβ). Because deposition of fibrillar amyloid in vitrohas been shown to be highly dependent on Aβ concentration, reducing the proteolytic release of Aβ is an attractive, potentially therapeutic target. Here, the turnover rate of brain Aβ has been determined to define treatment intervals over which a change in steady-state concentration of Aβ could be measured. Mice producing elevated levels of human Aβ were used to determine approximate turnover rates for Aβ and two of its precursors, C99 and APP. Thet½ for brain Aβ was between 1.0 and 2.5 hr, whereas for C99, immature, and fully glycosylated forms of APP695 the approximate t½ values were 3, 3, and 7 hr, respectively. Given the rapid Aβ turnover rate, acute studies were designed using phorbol 12-myristate 13-acetate (PMA), which had been demonstrated previously to reduce Aβ secretion from cells in vitro via induction of protein kinase C (PKC) activity. Six hours after intracortical injection of PMA, Aβ levels were significantly reduced, as measured by both Aβ40- and Aβ42-selective ELISAs, returning to normal by 12 hr. An inactive structural analog of PMA, 4α-PMA, had no effect on brain Aβ levels. Among the secreted N-terminal APP fragments, APPβ levels were significantly reduced by PMA treatment, whereas APPα levels were unchanged, in contrast to most cell culture studies. These results indicate that Aβ is rapidly turned over under normal conditions and support the therapeutic potential of elevating PKC activity for reduction of brain Aβ.