UC San Diego

Amyloid precursor protein (APP) is intimately involved in the pathogenesis of Alzheimer's disease (AD), a neurodegenerative disease characterized by cognitive decline, amyloid plaques, and neurofibrillary tangles. Beta-secretase cleavage of APP is the first step in the amyloidogenic cleavage pathway that is enhanced in AD and generates amyloid beta peptides, the primary component of amyloid plaques. It is not clear how this enhanced amyloidogenic cleavage of APP can lead to AD pathology, but research has indicated that defects in axonal transport may contribute to disease progression. Signs of axonal transport defects develop in AD and animal models of amyloid pathology well before amyloid plaques deposit. It remains unknown how increased beta-secretase cleavage affects APP axonal transport and can lead to axonal defects. This thesis project shows that enhanced beta- secretase cleavage of APP impairs APP axonal transport in vitro and leads to axonal dystrophy in vivo, suggesting that disrupted axonal transport of APP might contribute to disease pathogenesis. First, I used a fluorescently-tagged version of the APP protein to show that 1) the familial AD (FAD) Swedish mutations at the beta-secretase cleavage site of APP increase beta-secretase cleavage and inhibit APP anterograde axonal transport, and 2) an opposing mutation at the beta-secretase cleavage site decreases beta-secretase cleavage and enhances APP anterograde axonal transport. Next, I used a gene-targeted mouse model to show that 1) FAD Swedish mutant APP expressed at endogenous levels can lead to axonal dilation in the cholinergic basal forebrain, and 2) axonal dystrophy develops in the absence of amyloid plaques. Taken together, these data suggest that amyloidogenic cleavage of APP, which is enhanced in AD, disrupts APP axonal transport and leads to axonal dystrophy before amyloid plaque formation, presenting a possible mechanism contributing to AD pathogenesis