Winning Abstracts from the 2012 Medical Student Abstract Competition: The Study of Neuronal Sensitivity to Ischemic Damage in a Transgenic Mouse Model of Alzheimer's Disease
Author: Rung-Chi Li, Touro University College of Osteopathic Medicine California, Class of 2013
Introduction: Accumulating evidence has linked stroke and Alzheimer’s disease (AD) and shown that each exacerbates the severity of the other. Recent studies suggest that vascular effects (such as vascular reactivity and inflammation) may play an important role in AD pathophysiological progression. The original concept that AD is a purely neurologically driven disorder has been questioned based on this strong connection between AD and stroke. It is challenging to completely separate the vascular and neurological system and independently to investigate the importance of each system in the AD pathology. We proposed here to use an acute brain slice preparation to directly examine neuronal synaptic properties under controlled conditions, by removing the need for the vascular system for delivery of oxygen and glucose. This method avoids the possible effects of amyloid on vascular dysfunction. Therefore, using oxygen glucose deprivation we can investigate whether ischemic neuronal damage in a triple transgenic mouse model of AD is due to intrinsic neuronal sensitivity to ischemia or has contributions from vascular dysfunction.
Methods: Ischemic damage was modeled using oxygen-glucose deprivation (OGD; an in vitro global cerebral ischemia model) in brain slices from mice with an APP/PS1/tau triple gene mutation, an aggressive model of AD. These mice develop amyloid plaques at about 2-3 months of age, and behavioral memory deficits are developed by 6 months of age.
Results: Our results have demonstrated a significantly higher maximum recovery rate after OGD for 7.5 minutes in 3.5 month-old AD mice compared to the wild-type cohorts. More interestingly, 8 month-old AD mice group subjected to 5 minutes OGD insult showed a similar trend, compared to age-matched wild-type cohorts. In contrast, we did not observe any difference between WT and AD 8-month-old mice for 7.5 minutes OGD. These results suggest that the hippocampal slices from transgenic mice show less sensitivity to OGD, indicating that the sensitivity seen in AD mice subject to vascular-occlusion models of ischemia may be due primarily to vascular factors rather than intrinsic neuronal sensitivity.
Conclusion: The observed changes in electrophysiological responses to OGD may reflect compensatory mechanisms in response to disease state similar to those seen in classic models of ischemic preconditioning. Such compensations may confer direct neuronal protection against stressors such as ischemia without improving vascular deficiencies that might lead to chronic hypoperfusion of AD brains. The current findings provide a new understanding of the close relationship between neuronal and vascular contributions to AD.
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