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Abstract
Neurodegenerative tauopathies are characterized by pathological accumulation of highly phosphorylated isoforms of tau protein, which leads to progressive neuronal loss. Neuroinflammation often accompanies tau-driven diseases; however, the direct role of neuroinflammation in tauopathies remains unknown. The 5-lipoxygenase (5LO) is a pro-inflammatory enzyme, which produces several bioactive metabolites and is widely expressed in the central nervous system. Previously, our group showed that 5LO influences the Alzheimer’s disease (AD) phenotype of APP transgenic mice as well as a mouse model with plaques and tangles. However, whether this protein directly modulates tau phosphorylation and subsequent neuropathology remains to be fully investigated. In the current study, we provide evidence for an age-dependent and region-specific upregulation of the 5LO pathway (protein, message and activity) in a transgenic mouse model of tauopathy, the P301S line. In addition, we demonstrate that genetic deletion of 5LO in this mouse model results in significant memory improvement, reduces tau phosphorylation at specific epitopes as well as neuroinflammation and rescues synaptic pathology. In vitro studies confirmed that 5LO directly modulates tau phosphorylation at the same epitopes as for the brain tissues. Taken together, our data reveal an active involvement of the 5LO pathway in the development of the tauopathy phenotype and provide strong support to the hypothesis that this enzymatic protein should be considered a novel and viable therapeutic target for the treatment of human tauopathy.
Highlights
The classic pathologic hallmark lesions in the Alzheimer’s disease (AD) brain are composed of pathogenic amyloid-beta (Aβ) peptides and tau protein, which lead to formation and deposits of Aβ plaques and neurofibrillary tangles, respectively[1]
At the end of these studies, we found that the genetic absence of 5LO rescued behavioral deficits, tau phosphorylation, as well as synaptic pathology and neuroinflammation in P301S mice
To assess the expression levels of the 5LO pathway in the P301S mice, we first measured levels of its protein in different brain regions of these mice and matched WT controls when they were 2, 5, 8 and 12 months of age (n = 6 per group, per age, equal number males and females) As shown in Fig. 1a, steady-state levels of 5LO protein were significantly increased in both brain cortex and hippocampus of P301S mice at 8 and 12 months of age compared to WT controls
Summary
The classic pathologic hallmark lesions in the Alzheimer’s disease (AD) brain are composed of pathogenic amyloid-beta (Aβ) peptides and tau protein, which lead to formation and deposits of Aβ plaques and neurofibrillary tangles, respectively[1]. Because of some disappointing results of the Aβ-centered therapies, research has focused on the tau protein and its role in the pathogenesis of AD and related tauopathies. Human neurodegenerative tauopathies, which include a variety of diseases such as progressive supranuclear palsy (PSP), Pick’s disease and corticobasal degeneration, display progressive accumulation of hyper-phosphorylated tau protein and pathology together with cognitive impairments and synaptic loss in the absence of Aβ accumulation[2,3]. While compelling evidence has emerged linking inflammatory pathways to neurodegeneration in both human and mouse models of tauopathy, the source of the neuroinflammation and whether it is a primary or secondary event in disease progression, has yet to be fully elucidated[4,5,6]. Our group has demonstrated a role for 5LO in the development of the AD-like phenotype in transgenic mouse
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