Up-regulation of neurofilament light chains is associated with diminished immunoreactivities for MAP2 and tau after ischemic stroke in rodents and in a human case.

As stroke therapies are still limited to a minority of patients, efforts have been intensified to an improved understanding of pathophysiological processes during ischemia formation, potentially allowing the development of specific therapeutic interventions. In this context, cytoskeletal elements became evident as key players during the transition process towards long-lasting tissue damage. This study focused on ischemia-related alterations of the cytoskeleton with a special focus on microtubule-associated proteins and neurofilament light chains (NF-L). Immunohistochemical analyses were applied to brain sections of mice and rats after experimental stroke and to autoptic samples from a stroke patient. To consider translational aspects, a thromboembolic model of stroke in rats, closely mimicking the human situation, was used in addition to the filament-based model of focal cerebral ischemia in mice. One day after ischemia onset, immunoreactivity of microtubule-associated protein tau and microtubule-associated protein-2 (MAP2) was reduced in ischemic areas. These findings were consistently present in the ischemia-affected striatum and the neocortex. In a quite opposite fashion, ischemic areas displayed NF-L-immunoreactivity in neuropathologically altered fibers, local agglomerations probably related to degraded cell bodies and neocortical pyramidal cells. Notably, up-regulation of NF-L was also confirmed in infarcted tissue from a human brain sample. Furthermore, analyses of rodent brain tissue revealed corkscrew curl-like fibers as a special feature of MAP2 in the ischemia-affected hippocampus. In conclusion, this study provides evidence for an opposite reaction of microtubule-associated proteins and neurofilaments after focal cerebral ischemia. Accordingly, cytoskeletal elements appear as a promising target for stroke treatment.

Decline of microtubule-associated protein tau after experimental stroke in differently aged wild-type and 3xTg mice with Alzheimer-like alterations.

Stroke therapies are still limited to a minority of patients. Considering time-dependent aspects of stroke, the penumbra concept describes the transition from functional to permanent tissue damage. Thereby, the role of cytoskeletal elements, as for instance microtubules with associated tau remains poorly understood and is therefore not yet considered for therapeutic approaches. This study explored the expression of microtubule-associated protein tau related to neuronal damage in stroke-affected brain regions. Wild-type and triple-transgenic mice of 3, 7 and 12months of age and with an Alzheimer-like background underwent experimental stroke. After 24h, brain sections were used for immunofluorescence labeling of tau and Neuronal Nuclei (NeuN). Potential functional consequences of cellular alterations were explored by statistical relationships to the general health condition, i.e. neurobehavioral deficits and loss of body weight. Immunoreactivity for whole tau decreased significantly in ischemic areas, while the decline at the border zone was more drastic for tau-immunoreactivity compared with the diminished NeuN labeling. Quantitative analyses confirmed pronounced sensitivity for tau-immunoreactivity in the ischemic border zone. Decline of tau- as well as NeuN-immunoreactivity correlated with body weight loss during the 24-h observation period. In conclusion, microtubule-associated protein tau was robustly identified as a highly sensitive cytoskeletal constitute under ischemic conditions, suggesting a pivotal role during the transition process toward long-lasting tissue damage. Consequently, cytoskeletal elements appear as promising targets for novel therapeutic approaches with the objective to impede ischemia-induced irreversible cellular degradation.