دانلود رایگان مقاله تغییر روند پیری با هیپوکامپ و قشر سکرتاز فعالیت موش صحرایی

Abstract

 A growing body of evidence has demonstrated amyloid plaques in aged brain; however, little attention has been given to amyloid precursor protein (APP) processing machinery during the healthy aging process. The amyloidogenic and non-amyloidogenic pathways, represented respectively by - and - secretases (BACE and TACE), are responsible for APP cleavage. Our working hypothesis is that the normal aging process could imbalance amyloidogenic and non-amyloidogenic pathways specifically BACE and TACE activities. Besides, although it has been showed that exercise can modulate secretase activities in Alzheimer Disease models the relationship between exercise effects and APP processing during healthy aging process is rarely studied. Our aim was to investigate the aging process and the exercise effects on cortical and hippocampal BACE and TACE activities and aversive memory performance. Young adult and aged Wistar rats were subjected to an exercise protocol (20 min/day for 2 weeks) and to inhibitory avoidance task. Biochemical parameters were evaluated 1 h and 18 h after the last exercise session in order to verify transitory and delayed exercise effects. Aged rats exhibited impaired aversive memory and diminished cortical TACE activity. Moreover, an imbalance between TACE and BACE activities in favor of BACE activity was observed in aged brain. Moderate treadmill exercise was unable to alter secretase activities in any brain areas or time points evaluated. Our results suggest that aging-related aversive memory decline is partly linked to decreased cortical TACE activity. Additionally, an imbalance between secretase activities can be related to the higher vulnerability to neurodegenerative diseases induced by aging.

4. Discussion

Our work adds evidence for the role of non-amyloidogenic and amyloidogenic pathways, specifically of secretases in the aging process. In addition, to our knowledge, this is the first study evaluating TACE activity in healthy aged brains. In this context, we observed a diminished -secretase activity, specifically TACE (ADAM17). Consistent with our results, lower soluble APP (sAPP) levels, a TACE-derived product, have been found in cerebrospinal fluid (CSF) of 23-month-old rats [19]. Moreover, individuals with Alzheimer’s disease present low sAPP levels in the CSF suggesting reduced TACE-dependent -secretase activity [40,41]. Taken that sAPP appears to have beneficial functions including neuroprotection, neurotrophism and neurogenesis [19,42], it is possible to suppose that reduced TACE activity observed here in aged prefrontal cortices and hippocampus might be implicated in their susceptibility to neurodegenerative disorders. We can suggest that the memory impairment in aged rats, as evaluated by an inhibitory avoidance test, may be related to cortical TACE activity, since this parameter was reduced in prefrontal cortices of 21-and 26-month-old rats while in hippocampus this reduction was observed only in oldest rats (26-month-old rats). In accordance, Anderson et al. [19] showed the involvement of sAPP levels in the cerebrospinal fluid (CSF) with better spatial cognitive performance in aged rats. Our data support the idea that decreases in cortical -secretase (TACE)-mediated cleavage of APP, a non-amyloidogenic pathway, may be partly involved in the agingrelated aversive memory decline. In add