Amyloid-beta (Abeta) appears critical to Alzheimer's disease. To clarify possible mechanisms of Abeta action, we have quantified Abeta-induced gene expression in vitro by using Abeta-treated primary cortical neuronal cultures and in vivo by using mice transgenic for the Abeta precursor (AbetaP). Here, we report that aggregated, but not nonaggregated, Abeta increases the level of the mRNAs encoding tissue plasminogen activator (tPA) and urokinase-type plasminogen activator (uPA). Moreover, tPA and uPA were also upregulated in aged AbetaP overexpressing mice. Because others have reported that Abeta aggregates can substitute for fibrin aggregates in activating tPA post-translationally, the result of tPA induction by Abeta would be cleavage of plasminogen to the active protease plasmin. To gain insights into the possible actions of plasmin, we evaluated the hypotheses that tPA and plasmin may mediate Abeta in vitro toxicity or, alternatively, that plasmin activation may lead to Abeta degradation. In evaluating these conflicting hypotheses, we found that purified plasmin degrades Abeta with physiologically relevant efficiency, i.e., approximately 1/10th the rate of plasmin on fibrin. Mass spectral analyses show that plasmin cleaves Abeta at multiple sites. Electron microscopy confirms indirect assays suggesting that plasmin degrades Abeta fibrils. Moreover, exogenously added plasmin blocks Abeta neurotoxicity. In summation, we interpret these results as consistent with the possibility that the plasmin pathway is induced by aggregated Abeta, which can lead to Abeta degradation and inhibition of Abeta actions.

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Substance P (SP) is an 11-amino-acid neuropeptide found in sensory neurons in the peripheral nervous system. In addition to having well-characterized functions as a peptide neurotransmitter, it also plays a major role in modulating inflammatory and immune responses. SP can alter the proliferative and physiological responses of both lymphocytes and macrophages. These effects are mediated by specific high-affinity SP receptors which have been characterized both kinetically and biochemically. The principle SP binding protein present on human lymphocyte cell membranes is a 58,000-MW hydrophobic glycoprotein. Cellular responses subsequent to the binding of substance P to its receptor that have been identified in various cell populations include phosphatidyl inositol turnover, arachidonic acid metabolism, immunoglobulin synthesis, and enzyme production and secretion. Evidence also suggests that SP modulation of inflammation is a factor in the pathophysiology of certain diseases such as rheumatoid arthritis.

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The mitogenic effect of corticotropin-releasing factor (CRF) on rat lymphocytes was investigated. When rat splenocytes were cultured for 48 hr with CFR, a dose-dependent increase in incorporation of 3H-thymidine (3H-Tdr) was observed, with a maximal response at 10 nM CRF. Comparison of the proliferative effect of CRF on enriched populations of B lymphocytes, T lymphocytes, or macrophages revealed that only B lymphocytes responded following treatment with CRF. When lymphocytes derived from different lymphoid tissues were compared, CRF had a greater proliferative effect on lymphocytes derived from gut-associated lymphoid tissue (mesenteric lymph nodes and Peyer's patches) than on lymphocytes from spleen or inguinal lymph nodes; CRF had no effect on thymocytes. Synthetic fragments of CRF were used to determine which portions of the peptide are recognized by lymphocytes. The C-terminal fragments alpha-helical CRF9-41 and CRF21-41 were as potent as native CRF in stimulating B-lymphocyte proliferation, whereas CRF1-20 did not stimulate proliferation. The activity of these peptides suggests that CRF stimulates lymphocyte proliferation by cellular recognition of structural determinants in the C-terminal one-half of the peptide.

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