Investigating the potential significance of tau protein in corticosterone-induced depression and neurodegeneration : implication in Alzheimer's disease

Abstract

Alzheimer’s disease (AD) is a devastating neurodegenerative disease with growing prevalence in our society. Patients suffering from this debilitating disorder also develop neuropsychiatric symptoms. Depression is one of the most frequently conveyed comorbidity; moreover, depression is also a risk factor associated with AD development. There is a complex interplay between the neurobiology of depression and AD, but their concomitant disease mechanisms remain largely unknown. Retraction of axons and dendrites has been reported to be a common occurrence in both illnesses, proposing the involvement of cytoskeletal dysfunction.

Tau is a microtubule-associated protein that undergoes aberrant processing to form neurofibrillary tangles in neurodegenerative diseases such as AD. However, the role of tau in depression has not been well studied. The elucidation of pathophysiological mechanisms in depression is important to provide a more holistic understanding of AD pathogenesis. This study proposes the potential participation of tau phosphorylation in the pathogenesis of depression. In addition, this study will also investigate tau modifications under concomitant models of depression and AD.

Primary cultures of hippocampal neurons were exposed to independent and cotreatments of corticosterone and β-amyloid (Aβ), to induce in vitro models of depression and AD, respectively. Sprague Dawley rats were subcutaneously injected with corticosterone for 14 days to induce an in vivo model of depression. Tau phosphorylation, aggregation and interaction with microtubules were examined.

Results demonstrated that in both in vitro and in vivo models of corticosterone-induce depression, tau underwent increased phosphorylation at residues S396 and S404. Phosphorylated tau showed decreased interactions with microtubules and increased vulnerability to aggregate. Furthermore, the in vivo model of depression illustrated an altered localization of tau in the CA3 region of the hippocampus. Co-treatment of corticosterone and Aβ exacerbated aberrant tau phosphorylation and aggregation.

In conclusion, this study provides evidence for the role of tau in depression, suggesting the occurrence of abnormal tau phosphorylation as an early event in the pathogenesis. Additionally, the pathophysiology of depression and AD may involve similar mechanisms in tau phosphorylation and aggregation. This study provides insight into the neurobiological linkages between depression and AD, and emphasizes the importance of tau-targeted interventions in neuropsychiatric disorders.