Migration of activated macrophages is essential for resolution of acute inflammation and the initiation of adaptive immunity. Here, we show that efficient macrophage migration in inflammatory environment depends on Mac-1 recognition of a binary complex consisting of fibrin within the provisional matrix and the protease tPA (tissue-type plasminogen activator). Subsequent neutralization of tPA by its inhibitor PAI-1 enhances binding of the integrinprotease-inhibitor complex to the endocytic receptor LRP (lipoprotein receptor-related protein), triggering a switch from cell adhesion to cell detachment. Genetic inactivation of Mac-1, tPA, PAI-1 or LRP but not the protease uPA abrogates macrophage migration. The defective macrophage migration in PAI-1-deficient mice can be restored by wild-type but not by a mutant PAI-1 that does not interact with LRP. In vitro analysis shows that tPA promotes Mac-1-mediated adhesion, whereas PAI-1 and LRP facilitate its transition to cell retraction. Our results emphasize the importance of ordered transitions both temporally and spatially between individual steps of cell migration, and support a model where efficient migration of inflammatory macrophages depends on cooperation of three physiologically prominent systems (integrins, coagulation and fibrinolysis, and endocytosis).
The amyloid precursor protein (APP) is cleaved to produce the Alzheimer disease-associated peptide A, but the normal functions of uncleaved APP in the brain are unknown. We found that APP was present in the postsynaptic density of central excitatory synapses and coimmunoprecipitated with N-methyl-Daspartate receptors (NMDARs). The presence of APP in the postsynaptic density was supported by the observation that NMDARs regulated trafficking and processing of APP; overexpression of the NR1 subunit increased surface levels of APP, whereas activation of NMDARs decreased surface APP and promoted production of A. We transfected APP or APP RNA interference into primary neurons and used electrophysiological techniques to explore the effects of APP on postsynaptic function. Reduction of APP decreased (and overexpression of APP increased) NMDAR whole cell current density and peak amplitude of spontaneous miniature excitatory postsynaptic currents. The increase in NMDAR current by APP was due to specific recruitment of additional NR2B-containing receptors. Consistent with these findings, immunohistochemical experiments demonstrated that APP increased the surface levels and decreased internalization of NR2B subunits. These results demonstrate a novel physiological role of postsynaptic APP in enhancing NMDAR function.Alzheimer disease (AD) 5 is an age-related neurodegenerative disease characterized by the progressive loss of synapses and neurons and by the formation of amyloid plaques and neurofibrillary tangles. Amyloid plaques are composed predominantly of the A peptide, a 40-or 42-amino acid cleavage product of amyloid precursor protein (APP). APP is a transmembrane protein of unknown function that undergoes extracellular cleavage by one of two activities, ␣-or -secretase, resulting in the formation of large N-terminal extracellular fragments of secreted APP and smaller, membrane-bound C-terminal fragments. If the initial cleavage event occurs via -secretase, then subsequent cleavage of the C-terminal fragment by ␥-secretase results in the production of A (1).Clues to APP function may be gleaned from studies of its different cleavage products or isoforms. Soluble forms of APP have been found to be neurotrophic, and some splice variants have proteinase inhibitor activity (2). The APP intracellular domain may alter gene transcription in conjunction with cytoplasmic proteins (3). In addition, the A peptide has been shown to inhibit glutamate receptor activity (4, 5). However, the function of full-length APP is undefined, and it is likely that full-length APP performs distinct roles from any its cleavage products. One recent study showed that mice lacking APP have impaired development of neuromuscular junctions (6), suggesting an important role for APP in maintaining active synapses. Understanding APP function in central neurons may provide valuable information in generating interventions against the generation of A and thus AD pathogenesis and its accompanying memory loss.Further evidence for a synaptic function of A...
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