Alzheimer's disease (AD) is a fatal form of dementia exhibiting two major cellular pathologies: extracellular amyloid plaques (comprised of amyloid-beta, a cleavage product of amyloid precursor protein (APP)), and intracellular neurofibrillary tangles, aggregates of hyperphosphorylated tau (a microtubule-regulatory protein). The mechanistic links between these pathologies are not yet known, but some evidence implicates the APP intracellular domain (AICD) in mediating tau phosphorylation and neuron death. Another process linked to AD and other neurodegenerative diseases is inflammation. The research presented here investigated the ability of AICD and inflammation to alter tau phosphorylation. AICD overexpression was not found to be toxic in PC12 cells, nor did it alter tau phosphorylation. However, AICD overexpression in primary neuronal cultures did affect tau biochemistry, indicating that this fragment can have disparate roles in different cellular contexts. A cell-culture approximation of the neuroinflammatory state, based on treatment with individual pro-inflammatory cytokines, showed that treatment with TNFalpha is toxic without affecting tau phosphorylation, while IL-6 is capable of increasing phosphorylation. Together, these data demonstrate the importance of cellular context in determining the function of AICD, as well as the complexity of the inflammatory process in potentiating tau-related neurodegenerative disease. Further investigations of the contributions of AICD and neuroinflammation to tau pathology may enable a more integrated depiction of the mechanism of AD. In one final study, it was observed that tau overexpression in primary neurons leads to neurite fragmentation.