To clarify the role of microglia in brain homeostasis and disease, an understanding of their maintenance, proliferation and turnover is essential. The lifespan of brain microglia, however, remains uncertain, and reflects confounding factors in earlier assessments that were largely indirect. We genetically labeled single resident microglia in living mice and then used multiphoton microscopy to monitor these cells over time. Under homeostatic conditions, we found that neocortical resident microglia were long-lived, with a median lifetime of well over 15 months; thus, approximately half of these cells survive the entire mouse lifespan. While proliferation of resident neocortical microglia under homeostatic conditions was low, microglial proliferation in a mouse model of Alzheimer's β-amyloidosis was increased threefold. The persistence of individual microglia throughout the mouse lifespan provides an explanation for how microglial priming early in life can induce lasting functional changes and how microglial senescence may contribute to age-related neurodegenerative diseases.
Summary Ectodomain (EC) shedding defines the proteolytic removal of a membrane protein EC and acts as an important molecular switch in signaling and other cellular processes. Using tumor necrosis factor (TNF)α as a model substrate, we identify a non-canonical shedding activity of SPPL2a, an intramembrane cleaving aspartyl protease of the GxGD type. Proline insertions in the TNFα transmembrane (TM) helix strongly increased SPPL2a non-canonical shedding, while leucine mutations decreased this cleavage. Using biophysical and structural analysis, as well as molecular dynamic simulations, we identified a flexible region in the center of the TNFα wildtype TM domain, which plays an important role in the processing of TNFα by SPPL2a. This study combines molecular biology, biochemistry, and biophysics to provide insights into the dynamic architecture of a substrate's TM helix and its impact on non-canonical shedding. Thus, these data will provide the basis to identify further physiological substrates of non-canonical shedding in the future.
Because we previously found increased basal serum cortisol levels in women runners, we examined adrenocortical function in amenorrheic running women (AR), eumenorrheic running women (R), and normal nonexercising women (NC) in further detail. Mean 24-h urinary cortisol levels were significantly elevated (P less than 0.001) in six AR [45.1 +/- 7.2 (+/- SEM) micrograms/24 h] and eight R (38.5 +/- 6.9 micrograms/24 h) compared to four NC (13.9 +/- 2.8 micrograms/24 h). After adrenal suppression with 2 mg dexamethasone, integrated responses and absolute maximal elevations in serum cortisol levels in response to 10 micrograms/m2 exogenous ACTH (1-24) administered as an iv bolus dose, were not significantly different among six AR, six R, and six NC. This dose of ACTH results in maximal steroid release. The disappearance rates of cortisol (5 mg, iv) after dexamethasone suppression were similar in four AR, five R, and four NC and corresponded to a two-compartment model with mean half-lives of 4.9 and 93.8 min, respectively. Cortisol-binding globulin levels were also similar among the groups. These data document higher cortisol secretion and suggest increased ACTH secretion in running women.
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