The amyloid precursor protein (APP) of Alzheimer disease and its paralog, APLP2, modulate the Cu/Zn-Nitric Oxide-catalyzed degradation of glypican-1 heparan sulfate in vivo

Processing of the recycling proteoglycan glypican-1 involves the release of its heparan sulfate chains by copper ion- and nitric oxide-catalyzed ascorbate-triggered autodegradation. The Alzheimer disease amyloid precursor protein (APP) and its paralogue, the amyloid precursor-like protein 2 (APLP2), contain copper ion-, zinc ion-, and heparan sulfate-binding domains. We have investigated the possibility that APP and APLP2 regulate glypican-1 processing during endocytosis and recycling. By using cell-free biochemical experiments, confocal laser immunofluorescence microscopy, and flow cytometry of tissues and cells from wild-type and knock-out mice, we find that (a) APP and glypican-1 colocalize in perinuclear compartments of neuroblastoma cells, (b) ascorbate-triggered nitric oxidecatalyzed glypican-1 autodegradation is zinc ion-dependent in the same cells, (c) in cell-free experiments, APP but not APLP2 stimulates glypican-1 autodegradation in the presence of both Cu(II) and Zn(II) ions, whereas the Cu(I) form of APP and the Cu(II) and Cu(I) forms of APLP2 inhibit autodegradation, (d) in primary cortical neurons from APP or APLP2 knock-out mice, there is an increased nitric oxide-catalyzed degradation of heparan sulfate compared with brain tissue and neurons from wild-type mice, and (e) in growth-quiescent fibroblasts from APLP2 knock-out mice, but not from APP knock-out mice, there is also an increased heparan sulfate degradation. We propose that the rate of autoprocessing of glypican-1 is modulated by APP and APLP2 in neurons and by APLP2 in fibroblasts. These observation identify a functional relationship between the heparan sulfate and copper ion binding activities of APP/APLP2 in their modulation of the nitroxyl anion-catalyzed heparan sulfate degradation in glypican-1.     

Ixodes rubicundus nymphs are short-day diapause-induced ticks with thermolabile sensitivity and desiccation resistance

The Karoo Paralysis tick, Ixodes rubicundus Neumann (Acari: Ixodidae), is a semi-voltine ixodid that survives stressful environmental conditions using morphogenetic diapause (eggs and engorged nymphs) and desiccation resistance. Both photoperiod and temperature influence diapause induction in the engorged nymph. Ixodes rubicundus nymphs are typical long-day photoperiodic organisms. The critical photoperiod is approximately 13.5 h light, 10.5 h dark, and they display a thermolabile response. The period between detachment and apolysis in engorged nymphs is modified by photoperiod; however, apolysis to ecdysis is not affected by photoperiod. Thus, initiation of development, but not the actual process is controlled by photoperiod. Most engorged nymphs delayed metamorphosis when exposed to short-day regimen (LD 12 : 12 h) after feeding. Nymphs exposed to pre- and post-feeding long-day regimen (LD 14 : 10 h) developed. Times for 50% of nymphs to apolyse when exposed to photoperiods of LD 14 : 10 h, 13.5 : 10.5 h, 13 : 11 h and 12 : 12 h were 28, 36, 40 and 58 days, respectively. Times for 50% of engorged nymphs to ecdyse ranged from 38 to 40 days after apolysis. Nymphs were sensitive to photoperiodic exposures before, during and after feeding. Nymphs exposed to long day (LD 14 :10 h) before and during feeding, moulted at 20 degrees C; however, most exposed to 10 degrees C followed by 20 degrees C (post-feeding) went into diapause. Both short- (10 : 14 h) and long- (14 : 10 h) day exposed engorged nymphs survived 45 days at 0% r.h. (n = 73), but diapause-destined ticks kept at 13 degrees C lost the least mass (29.5+/-9.5%, SD), while nondiapause ticks at 23 degrees C lost the most (48.7+/-8.2%, SD). Termination of diapause and transition to development probably coincides with a definite increase of water vapour uptake by engorged nymphs. Comparatively, I. rubicundus engorged nymphs are more desiccation tolerant than a North-American counterpart, Amblyomma cajennense (Fabricius) (Acari: Ixodidae), which is also semi-arid- to xeric-adapted. Diapause conveys important survival attributes that enable engorged I. rubicundus nymphs to inhabit a semi-arid environment with great temperature extremes, and to synchronize their activity periods with seasons and host utilization patterns.