Title: Mechanisms underlying Abeta- and tau-induced neuronal degeneration in Alzheimer's disease
Description: Alzheimer's disease (AD) is associated with the neurological deposition of amyloid plaques and neurofibrillary tangles, which are primarily composed of the Aβ peptide and the microtubule-associated protein tau, respectively. The role of Aβ and tau in AD is now well supported although the specific means by which these proteins cause disease are unclear. The work in this thesis was undertaken to better understand how Aβ and tau contribute to neurodegeneration and disease progression in animal models of AD and related disorders. As described in chapter 2, coexpression of Aβ and tau in a Drosophila model of AD suggests that the two proteins interact genetically in a synergistic manner to promote neurodegeneration. The enhanced toxicity is likely due to an activation of tau by Aβ as the interaction is dependent on tau phosphorylation and mediated by tau-induced changes in the actin cytoskeleton. Tau-induced changes and neurodegeneration can also be potentiated by destabilization of the lysosomal system, as shown in chapter 3. The genetic depletion of cathepsin D, which mimics lysosomal abnormalities present in AD, leads to increased caspase-cleavage of tau, tau-induced cell cycle activation, and cell death in tau-expressing flies. Finally in chapter 4, a novel in vitro approach is described for generating primary Drosophila neuronal cultures that can be used to study the molecular pathways underlying neurodegeneration downstream of Aβ, tau or the two molecules in conjunction. Taken together, the chapters presented herein provide novel mechanistic insight into the means by which Aβ and tau act individually and in tandem to cause neurotoxicity and degeneration in Alzheimer's disease.