University of Tasmania, Australia

AD is the most intensely investigated nervous system disease within the neuroscience research community. Thus, tremendous advances have been achieved in our understanding of aspects of the AD process, such as the molecular genetics of familial AD and the protein composition of the principal characteristic lesions. The latter includes extracellular ß-amyloid (Aß) deposits and intracellular ‘neurofibrillary’ changes such as tangles, dystrophic neurites and neuropil threads. A major question remains as to the relationship between these pathological changes and the process by which specific subgroups of neurons slowly degenerate, leading to the gradual and progressive emergence of the clinical features of AD-related dementia. In this respect, Aß plaque formation appears to be an early pathological brain change (reviewed in Vickers et al., 2000; 2009). We have recently determined for the first time that Aß plaque formation in the brain, particularly fibrillar rather than ‘diffuse’ plaques, is associated with focal demyelination, with loss of myelin localized to segments of dystrophic neurites associated with plaques (Mitew et al., 2010). This recent discovery may open up new vistas on the relationship between plaque formation and axonal pathology, potentially providing insight also into the generation of aberrant sprouting and the disruption of neural circuitry that underlies the establishment of dementia. Hence, our study examines the potential role of Aß to induce axon pathology in AD, focussing on two alternative hypotheses: Hypothesis 1 Aß causes demyelination and/or oligodendrocyte degeneration, which then leads to dystrophic neurite formation, or; Hypothesis 2 Aß causes dystrophic neurite formation which then leads to secondary demyelination. Our studies involve investigations of human and transgenic mouse material to determine whether Aß deposits cause focal demyelination of axonal segments, death of oligodendrocytes and/or death/ proliferation of oligodendrocyte precursors. Our in vitro studies are focuses on determining the toxicity of Aß on axons, oligodendrocytes and oligodendrocyte precursor cells and using compartmentalized/co-culture preparations to determine how Aß may affect the interrelationship between myelination and axonal health/ dystrophy.