Type-Dependent Oxidative Damage in Frontotemporal Lobar Degeneration: Cortical Astrocytes Are Targets of Oxidative Damage

Abstract

Oxidative injury and stress responses are common features of many neurodegenerative diseases. To assess oxidative stress responses in frontotemporal lobar degeneration (FTLD), we identified increased 4-hydroxynonenal (HNE) adducts using gel electrophoresis and Western blotting in frontal cortex samples in 6 of 6 cases of FTLD with the P301L mutation in the tau gene (FTLD-tau), in 3 of 10 cases with tau-negative ubiquitin-immunoreactive inclusions, and in 2 of 3 cases associated with motor neuron disease. Selectively increased lipoxidation-derived protein damage associated with altered membrane unsaturation and fatty acid profiles was verified by mass spectrometry in FTLD-tau and FTLD associated with motor neuron disease. All FTLD-tau and most cases with increased HNE-positive bands had marked astrocytosis as determined by glial fibrillary acidic protein (GFAP) immunohistochemistry and increased GFAP expression on Western blotting; 2 FTLD cases with tau-negative ubiquitin-immunoreactive inclusions and with increased GFAP expression did not have increased HNE adducts. Bidimensional gel electrophoresis, Western blotting, in-gel digestion, and mass spectrometry identified GFAP as a major target of lipoxidation in all positive cases; confocal microscopy revealed colocalization of HNE and GFAP in cortical astrocytes, superoxide dismutase 1 in astrocytes, and superoxide dismutase 2 in astrocytes and neurons in all FTLD types. Thus, in FTLD, there is variable disease-dependent oxidative damage that is prominent in FTLD-tau, astrocytes are targets of oxidative damage, and GFAP is a target of lipoxidation. Astrocytes are, therefore, crucial elements of oxidative stress responses in FTLD.

LX2343 alleviates cognitive impairments in AD model rats by inhibiting oxidative stress-induced neuronal apoptosis and tauopathy

“…On the other hand, tauopathy induces OS [40] . Some OS markers are notably increased in tauopathy, such as malondialdehyde and 4-hydroxynonenal [41][42][43] . The activation of antioxidant defenses is also observed in tauopathy [44,45] .…”

Chronic traumatic encephalopathy-integration of canonical traumatic brain injury secondary injury mechanisms with tau pathology

“…Oxidative stress is elevated in several tauopathies (Alavi Naini and Soussi-Yanicostas, 2015; Castellani et al, 1995; Litvan, 2004; Martinez et al, 2008a). It is well known that in the tauopathy AD, Aβ is capable of inducing oxidative stress, a process which is hypothesized to be upstream of the formation of pathologic tau (Giraldo et al , 2014).…”

“…Lipid peroxidation-derived aldehydes have been found to be elevated in the brains of several tauopathies (Butterfield et al, 2010; Lovell et al, 2001; Markesbery and Lovell, 1998; Martinez et al, 2008a; Martinez et al, 2008b; Montine et al, 1997; Muntane et al, 2006; Odetti et al, 2000; Sayre et al, 1997). In fact, in PSP, a tauopathy with paired helical filament morphology distinct from AD, significant increases in 4-HNE are correlated with tau aggregation, suggesting that accumulation of 4-HNE may contribute to impairment of tau degradation (Odetti et al , 2000).…”

Secondary Metabolites of Lichens as Both Anti-aggregative and Antioxidant Agents in Tauopathies

“…It was also described that ROS associated to tauopathies, such as malondialdehyde (MDA) or 4-hydroxynonenal (HNE), a specie linked to polyunsaturated fatty acids. [21,22].…”

“…It was also described that ROS associated to tauopathies, such as malondialdehyde (MDA) or 4-hydroxynonenal (HNE), a specie linked to polyunsaturated fatty acids. [21,22].In contrast, antioxidants can prevent ROS that are able to induce injury. However, there are synthetic antioxidants that have shown either to induced cell toxicity or mutagenesis [23].…”