Tau hyperphosphorylation and axonal damage induced by N,N-diethyldithiocarbamate (DEDTC) treatment along late postnatal development is followed by a rescue during adulthood

• Published in: Journal of neuroscience research 2010-04, Vol.88 (5), p.1083-1093
• Main Authors: Utrera, Juana, Junyent, Felix, de Lemos, Luisa, Pallàs, Merce, Camins, Antoni, Romero, Rafael, Auladell, Carme
• Format: Article
• Language: English
• Subjects: Age Factors; Aging - physiology; Amino Acid Sequence - physiology; Animals; Animals, Newborn; axonal damage; Axons - drug effects; Axons - metabolism; Axons - pathology; Blotting, Western; Brain - drug effects; Brain - growth & development; Brain - pathology; Chelating Agents - toxicity; Cyclin-Dependent Kinase 5 - drug effects; Cyclin-Dependent Kinase 5 - metabolism; DEDTC; Ditiocarb - analogs & derivatives; Ditiocarb - toxicity; Glycogen Synthase Kinase 3 - drug effects; Glycogen Synthase Kinase 3 - metabolism; Glycogen Synthase Kinase 3 beta; Immunohistochemistry; Mice; Microtubules - drug effects; Microtubules - metabolism; Microtubules - pathology; Nerve Regeneration - physiology; Phosphorylation - drug effects; Postnatal development; Recovery of Function - physiology; Serine - metabolism; tau phosphorylation; tau Proteins - chemistry; tau Proteins - drug effects; tau Proteins - metabolism; Wallerian Degeneration - chemically induced; Wallerian Degeneration - metabolism; Wallerian Degeneration - physiopathology
• ISSN: 0360-4012; 1097-4547; 1097-4547
• DOI: 10.1002/jnr.22284

Axonal degeneration has been described as the pathological hallmark of peripheral neuropathies induced by DEDTC. In addition, axonal damage has also been observed in the brain of mice treated daily with DEDTC along postnatal development, though with this experimental model there was observed to be axonal recovery after treatment, during the adulthood. To focus on this axonal dynamic activity, damage‐recovery, a key axonal protein, the microtubule associated protein tau, was analyzed in this DEDTC model. Tau is a phosphoprotein and its dynamic site‐specific phosphorylation is essential for its proper function; in fact, high levels are correlated with cell dysfunction. Furthermore, the levels of tau phosphorylation are associated with dynamic microtubules during periods of high plasticity. Thus, phosphorylated tau at two sites of phosphorylation, Ser199 and Ser396, were evaluated during the second week of postnatal development and throughout adulthood. The results obtained by Western blot made it evident that the levels of p‐tau Ser199 and p‐tau Ser396 were higher in treated mice than in controls. Interestingly, by immunohistochemistry there was shown to be an increase in p‐tau‐immunolabeling in neuronal soma together with axonal tract alterations in treated animals with respect to controls, and the analyses of GSK3β and cdk5 revealed an increase in its activity in DEDTC‐treated animals. Nevertheless, in the adult a general decline in p‐tau was observed together with a rescue of axonal tract. All these data support the idea that the axonal damage induced by DEDTC treatment along postnatal development is followed by an axonal rescue during adulthood. © 2009 Wiley‐Liss, Inc.