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Fifth International Conference
Monokines Reduce Accumulation of ß-Peptide in Cultured Vascular
Smooth Muscle Cells by Enhancing the Nonamyloidogenic Processing of ßAPP
J. Frackowiak*, B. Mazur-Kolecka, R.T. Carrolla, A. Chauhan, H.M.
NYS Institute for Basic Research in Developmental Disabilities, Staten Island,
NY 10314, aParke Davis, Ann Arbor, MI 48105.
Note: Janusz Frackowiak's talk will not be recorded.
Smooth muscle cells (SMCs) produce §-amyloid in leptomeningeal and
cerebral blood vessels in Alzheimer's disease (AD) and in aged humans and
dogs. ß-amyloidogenesis in AD has been suggested to be influenced
by various factors, including immunopathological mechanisms. Our finding
of cells with macrophage and leukocyte markers around amyloid-free blood
vessels, but not in the vicinity of amyloid-affected vessels, implied that
macrophages might protect against amyloid formation [Amyloid 1994:1:8-16].
Recently, we described accumulation of amyloid-§ peptide (Aß)
and formation of amyloid fibrils by cultured SMCs derived from leptomeningeal
and cerebral blood vessels from old dogs [Neurosci Lett 1995;183:120-123,
Brain Res 1995;676:225-230] and humans with AD [unpublished]. We used this
culture system of SMCs to study the effects of monokines on secretion and
accumulation of Aß and production and processing of ß-amyloid
precursor protein (ßAPP). Factors secreted by LPS-activated monocytes
or microglia caused reduced intracellular deposition of Aß, but had
only a slight effect on Aß secretion. The cellular content of bßAPP--predominantly
ßAPP751/770--was not altered, but the secretion of ßAPP into
culture media was increased twofold. The altered secretion of Aß and
ßAPP was correlated with decreased fluidity of cell membranes and
with activation of SMCs, as shown in the MTT reduction test. The factors
derived from monocytes and microglia also affected processing of ßAPP
in control cells, which did not accumulate Aß. To identify the active
factors, we studied the effects of PGE2 and purified recombinant monokines--IL-1,
IL-6, and TNF-a and TGF-ß--on SMCs. We found that IL-1, IL-6, and
TNF-a most effectively reduced intracellular accumulation of Aß in
SMCs and also altered processing of ßAPP. These data show that monokines
reduce accumulation of Aß in SMCs, probably by reducing intracellular
retention of Aß and by activating the nonamyloidogenic pathway of
ßAPP processing. Activated perivascular phagocytes may thus be the
source of factors that protect against vascular
ß-amyloidogenesis in AD.
Supported in part by funds from the NYS/OMRDD and a grant from the National
Institute on Aging, PO1 AGO 4220.