Ischemic white matter injuries underlie cognitive decline in the elderly and vascular dementia. Ischemia in the subcortical white matter is caused by chronic reduction of blood flow due to narrowing of small arterioles. However, it remains unclear how chronic ischemia leads to white matter pathology. We aimed to develop an in vitro model of ischemic white matter injury using organotypic slice cultures. Cultured cerebellar slices preserved fully myelinated white matter tracts that were amenable to chronic hypoxic insult. Prolonged hypoxia caused progressive morphological evidence of axonal degeneration with focal constrictions and swellings. In contrast, myelin sheaths and oligodendrocytes exhibited remarkable resilience to hypoxia. The cytoskeletal degradation of axons was accompanied by mitochondrial shortening and lysosomal activation. Multiple pharmacological manipulations revealed that the AMPA glutamate receptor, calpain proteolysis, and lysosomal proteases were independently implicated in hypoxia-induced axonal degeneration in our model. Thus, our in vitro model would be a novel experimental system to explore molecular mechanisms of ischemic white matter injury. Furthermore, we verified that the in vitro assay could be successfully utilized to screen for molecules that can ameliorate hypoxia/ischemia-induced axonal degeneration.
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