Abstract
Bilateral common carotid artery stenosis (BCAS) models the effects of compromised cerebral blood flow on brain structure and function in mice. We compared the effects of BCAS in aged (21 month) and young adult (3 month) female mice, anticipating a differentially more severe effect in the older mice. Four weeks after surgery there was a significant age by time by treatment interaction on the radial-arm water maze (RAWM; p = 0.014): on the first day of the test, latencies of old mice were longer compared to the latencies of young adult mice, independent of BCAS. However, on the second day of the test, latencies of old BCAS mice were significantly longer than old control mice (p = 0.049), while latencies of old controls were similar to those of the young adult mice, indicating more severe impairment of hippocampal dependent learning and working memory by BCAS in the older mice. Fluorescence staining of myelin basic protein (MBP) showed that old age and BCAS both induced a significant decrease in fluorescence intensity. Evaluation of the number oligodendrocyte precursor cells demonstrated augmented myelin replacement in old BCAS mice (p < 0.05) compared with young adult BCAS and old control mice. While microglia morphology was assessed as normal in young adult control and young adult BCAS mice, microglia of old BCAS mice exhibited striking activation in the area of degraded myelin compared to young adult BCAS (p < 0.01) and old control mice (p < 0.05). These findings show a differentially more severe effect of cerebral hypoperfusion on cognitive function, myelin integrity and inflammatory processes in aged mice. Hypoperfusion may exacerbate degradation initiated by aging, which may induce more severe neuronal and cognitive phenotypes.
Highlights
Improvements in public health have led to a dramatic increase in the human lifespan over the last century (Vaupel, 2010)
In this study we examined the effect of cerebral hypoperfusion on behavior and cognition, the integrity of brain white matter and activation of microglia in young adult and aged female mice
Reduced cerebral blood flow was induced by the Bilateral common carotid artery stenosis (BCAS) procedure whereby stenosis of both common arteries is achieved by means of 0.18 mm surgical steel coils wrapped around both arteries in the course of microsurgery by us as well as by others (Shibata et al, 2004, 2007; Nakaji et al, 2006; Nishio et al, 2010)
Summary
Improvements in public health have led to a dramatic increase in the human lifespan over the last century (Vaupel, 2010). This has been accompanied by increased risk for the development of neurodegenerative and neuropsychiatric disorders of late life, including cognitive impairment, dementia and depression (Beach et al, 2007; Roher et al, 2011; Kaup et al, 2016). A definitive pathological definition of VCI is lacking, it is generally accepted that cerebral vessel disease, including cerebral atherosclerosis and arteriolosclerosis, results in global and/or local cerebral hypoperfusion leading to cortical and subcortical infarcts (Brun, 1994; Kalaria, 2016). White matter lesions (WMLs) represent pathologically incomplete infarcts in white matter, are common in cerebral hypoperfusion states and are evident as white matter hyperintensities on MRI (Fernando et al, 2006)
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