UC San Diego

Alzheimer's Disease (AD) is a devastating neurodegenerative disease that currently affects more than 26 million people worldwide and is projected to triple in prevalence by 2015. As such it represents an enormous economic, medical, scientific, and emotional burden on society. Despite extensive efforts, there is no cure and current treatments are only effective at ameloriating symptoms without delaying the progression of disease. Part of the challenge may stem from the use of model systems that incompletely recapitulate human disease. The recently discovered technology of human induced pluripotent stem cells (hIPSCS) has reinvigorated investigators and brought hope to the fields of AD. The power of hIPSC technology is the ability to capture the genomes of individual with complex genetic diseases in a pluripotent cell with the ability to become any one of the body. By driving hIPSC down a neuronal lineage, we can grow human neurons and model AD in a dish in the relevant cell type. A hallmark of the polarized structure of a neuron is it long thin axon where a wide variety of cargo essential for proper neuronal viability must be transported correctly to and from the axon terminal. Perturbations of this complex neuronal process can have drastic consequences and, in fact, many neurological diseases are associated with defects in neuronals novel, neuron-specific sorting defects in hIPSC-derived neurons with familial AD mutations. Specifically, we see that toxic, intracellular accumulations of [Beta]CTFs,proteolytic products of the amyloid precursor protein (APP), mediate decreased endocytosis and transcytosis of APP itself and lipoproteins. That this is a common phenotype of many fAD mutations suggests that impaired axonal delivery of lipoproteins compromises synaptic maintenance in fAD. In a specific fAD mutation, PS1[Delta]E9, we analyzed the complex axonal transport behavior of a number of AD- relevant cargo including APP, BACE1, Rab5a, mitochondria, and lysosomes. We report that PS1[Delta]E9 mutant neurons have enhanced anterograde transport of APP, possibly because of increased phosphorylated JIP1, while having no differences in Rab5a, BACE1, or mitochondrial transport behavior. Importantly, these transport changes accompanied by decreased density of axonal acidic vesicles and implicates impaired clearance of toxic axonal cargo in AD pathogenesis