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. / published_or_final_version / Anatomy / Master / Master of Philosophy

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Indiana University-Purdue University Indianapolis (IUPUI) / Background: Persons with Mild Cognitive Impairment (PwMCI) battle progressive disengagement from personally meaningful activities that results in functional decline. Little is known about PwMCI experience of engaging in meaningful activities and relationships among MCI stage, confidence, depressive symptoms, and function. Daily Engagement of Meaningful Activity (DEMA) is a multicomponent, family-focused, tailored intervention designed to benefit PwMCI and their caregivers by facilitating goal identification, preserve engagement, and support adjustments to cognitive and functional changes. Objectives: The aims of this secondary analysis were to: (i) describe PwMCI experience of engagement in DEMA, (ii) evaluate for potential relationship among MCI stage, confidence, depressive symptoms, activity type, activity performance, physical function and (iii) evaluate ability of select outcomes to predict change in depressive symptoms and physical function, (iv) determine difference between participants when sub-grouped by ICF level. Methods: Mixed methodology was used to conduct a secondary analysis from the parent study. The parent study used a two-group randomized trial involving PwMCI and informal caregivers participating in the Indiana Alzheimer Disease Center DEMA program. Quantitative analysis (dyads: DEMA N=20, Information Support N = 20) examined outcomes at baseline, posttest and follow-up. Analysis employed: (i) Colaizzi's Method of empirical phenomenology to describe PwMCI experience of engagement in activity intervention related to perceptions of changes in confidence, activity performance, and physical function; (ii) Pearson's and Spearman's correlation to ascertain relationship; (iii) Linear regression to model the relationship between explanatory and dependent variables; (iv) Independent t-test to determine significant difference in activities and physical function. Results: Qualitative themes confirm improved awareness, adjustment, problem-solving, confidence and optimized function. Significant correlations were found at baseline and posttest for MCI stage, depressive symptoms, activity type and physical function. At posttest, change in self-rated performance predicted change in depressive symptoms. Additionally, those who engaged in activity at the ICF level of participation demonstrated a significant increase in confidence and physical function. Conclusion: Qualitative themes and quantitative results clearly indicate the positive impact of DEMA. Future research should employ a larger, randomized controlled longitudinal trial to ascertain DEMA impact on physical function, reduction of participation restriction and improved QOL.