Abstract
In the setting of ischemic stroke, the neurofilament subunit NF-L and the microtubule-associated protein MAP2 have proven to be exceptionally ischemia-sensitive elements of the neuronal cytoskeleton. Since alterations of the cytoskeleton have been linked to the transition from reversible to irreversible tissue damage, the present study investigates underlying time- and region-specific alterations of NF-L and MAP2 in different animal models of focal cerebral ischemia. Although NF-L is increasingly established as a clinical stroke biomarker, MAP2 serum measurements after stroke are still lacking. Therefore, the present study further compares serum levels of MAP2 with NF-L in stroke patients. In the applied animal models, MAP2-related immunofluorescence intensities were decreased in ischemic areas, whereas the abundance of NF-L degradation products accounted for an increase of NF-L-related immunofluorescence intensity. Accordingly, Western blot analyses of ischemic areas revealed decreased protein levels of both MAP2 and NF-L. The cytoskeletal alterations are further reflected at an ultrastructural level as indicated by a significant reduction of detectable neurofilaments in cortical axons of ischemia-affected areas. Moreover, atomic force microscopy measurements confirmed altered mechanical properties as indicated by a decreased elastic strength in ischemia-affected tissue. In addition to the results from the animal models, stroke patients exhibited significantly elevated serum levels of MAP2, which increased with infarct size, whereas serum levels of NF-L did not differ significantly. Thus, MAP2 appears to be a more sensitive stroke biomarker than NF-L, especially for early neuronal damage. This perspective is strengthened by the results from the animal models, showing MAP2-related alterations at earlier time points compared to NF-L. The profound ischemia-induced alterations further qualify both cytoskeletal elements as promising targets for neuroprotective therapies.
Highlights
As part of the neuronal cytoskeleton, neurofilaments, microtubules, and associated proteins maintain cellular stability and impact on critical neuronal functions, such as the regulation of axonal caliber [1,2,3], conduction velocity [4], axonal transport [5,6,7], and synaptic function [8]
microtubule-associated protein 2 (MAP2) and neurofilament-light chain (NF-L) have proven as ischemia-sensitive elements of the neuronal cytoskeleton in various studies [13, 20, 23, 36, 40, 41, 56], a simultaneous region- and time-dependent characterization among different models of focal cerebral ischemia is not yet available
Ischemia-associated alterations are comprehensively indicated by changes of NF-L- and MAP2related immunofluorescence intensity throughout the applied models in mice (Fig. 1)
Summary
As part of the neuronal cytoskeleton, neurofilaments, microtubules, and associated proteins maintain cellular stability and impact on critical neuronal functions, such as the regulation of axonal caliber [1,2,3], conduction velocity [4], axonal transport [5,6,7], and synaptic function [8]. Even though cytoskeletal derangements were described in the context of ischemic stroke [18,19,20,21,22,23], neurofilaments and microtubule-associated proteins have so far been largely neglected as targets for neuroprotective approaches
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