Investigating the pathological mechanisms linking depression and Alzheimer’s disease

Abstract

Background: Alzheimer’s disease (AD) is a devastating neurodegenerative disease characterized by the presence of tau tangles, amyloid beta plaques and neuroinflammation. Although the mechanisms underlying AD are not fully understand, several key risk factors for developing AD have been identified, such as depression. Previous work from our group, using a corticosterone-induced model of depression in rats, has found that depression leads to tau phosphorylation and its displacement from microtubules, mislocalization and aggregation within neurons. The aims of my project are to continue investigating whether depression leads to other pathological tau alterations, such as acetylation, and to investigate the relationship between tau and neuroinflammation in the context of depression, focusing on the complement and toll-like receptor (TLR) signaling pathways. Method: In this project, we are using a corticosterone-induced model of depression. Corticosterone is administered daily to Sprague-Dawley (SD) rats for 21 days. Afterwards, a series of behavioral tests are performed including the Open Field test, the Novel Object Recognition task and the Forced Swim Test to assess their anxiety, memory and depressive behaviors, respectively. Afterwards, brain samples are collected from the animals to conduct immunohistochemical analysis, qPCR and western blot. Result: Following 21 days of corticosterone administration, subjects display decreased adrenal and bodyweight, and anxiety-like behaviors. Thus far, qPCR data demonstrates that there are increases in TLR4, as well as downstream elements in its signaling pathway, in the hippocampus. Conclusion: In depression, alterations to the TLR4 signaling pathway are observed in the hippocampus. We will further investigate this pathway, its interplay with the complement system, and how these alterations impact tau pathology.