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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

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Note: Janusz Frackowiak's talk will not be recorded.

ABSTRACT

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cerebral blood vessels from old dogs [Neurosci Lett 1995;183:120-123, Brain Res 1995;676:225-230] and humans with AD [unpublished].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.