Affiliations:
Alzheimer’s Center at Temple, Department of Pharmacology, Lewis Katz School of Medicine, Temple University, Philadelphia, PA, USA
Correspondence:
[*]
Correspondence to: Domenico Praticò, MD, Alzheimer’s Center at Temple, 947, Medical Education and
Research Building, 3500 North Broad Street, Philadelphia, PA 19140, USA. Tel.: +1 215 707 9380; Fax: +1 215 707
9890; E-mail: [email protected].
Abstract: Tauopathies belong to a large group of neurodegenerative diseases characterized by progressive accumulation of hyperphosphorylated tau. Tau is a microtubule binding protein which is necessary for their assembly and stability. However, tau affinity for microtubules mainly depends on its phosphorylation status, which is the result of a delicate balance between kinases and phosphatases activity. Any significant changes in this equilibrium can promote tau fibrillation, aggregation, neuronal dysfunction, and ultimately neuronal loss. Despite intensive research, the molecular mechanism(s) leading to tau hyperphosphorylation are still unknown and there is no cure for these diseases. Development of an effective strategy that successfully prevents tau excessive phosphorylation and/or tau aggregation may offer a real therapeutic opportunity for these less investigated neurodegenerative conditions. Beside tau, chronic brain inflammation is a common feature of all tauopathies and 5-lipoxygenase, an inflammatory enzyme, is upregulated in brain regions affected by tau pathology. Recently, in vitro studies and preclinical investigations with animal models of tauopathy have implicated 5-lipoxygenase in the regulation of tau phosphorylation through activation of the cyclin-dependent kinase 5 pathway, supporting the novel hypothesis that this protein is a promising therapeutic target for the treatment of tauopathies. In this article, we will discuss the contribution of the 5-lipoxygenase signaling pathway in the development of tau neuropathology, and the promising potential that drugs targeting this enzyme activation hold as a novel disease-modifying therapeutic approach for tauopathies.
Keywords: 5-lipoxygenase, phosphorylation, tau protein, tauopathies
